Biopharmaceutics and Pharmacokinetics

1ST SEMESTER – PRELIM

TOPIC 1: Introduction to Biopharmaceutics LADMER SYSTEM

and Pharmacokinetics
 Series of processes which effectively describes
BIOPHARMACEUTICS
the journey or the movement of the drug
 It is the science that examines the inside our body.
interrelationship of the physicochemical  LIBERATION
properties of the drug, the dosage form in  ABSORPTION
Pharmacokinetics
which the drug is given, and the route of  DISTRIBUTION
Processes
administration on the rate and extent of  METABOLISM
systemic drug absorption.  EXCRETION
 It is the study of the chemical and physical  RESPONSE – Pharmacodynamics Process
properties of drugs, their components, and ø Drug Disposition – Distribution, Metabolism,
their activities in living organisms. and Excretion
 Rate and extent of systematic drug ø Drug Elimination – Metabolism and Excretion
absorption – also referred to as the
Liberation
<Bioavailability=
 Bioavailability – measure of the rate and  It is delivery of the active ingredient from a
extent of systemic drug absorption; how much dosage form into solution.
and how fast a drug is being absorbed by our  Drug release process
body.  Liberate means <to free=
 3 major factors that affect the rate and extent  In order to be able a drug to be absorbed by
of drug absorption/ drug’s bioavailability – (1) our body, it should be in a form of solution.
physicochemical properties of a drug, (2)
dosage form/ physical form of the drug
containing both inactive and active
ingredients

Pharmacokinetics

 It is the study of the time course of drug

movement in the body during absorption,
distribution, and elimination.
 Movement of drugs inside our body
 Derived from the Greek words <Pharmakon= =
drug; <kinetikos= = moving/movement 2 COMPONENTS OF LIBERATION
 A branch of pharmacology
 Pharmacology – general study of drugs and its  Disintegration - A state in which any residue
property of the tablet, except fragments of insoluble
 Pharmacodynamics – study of the coating, remaining on the screen of the test
biochemical and physiologic effects of apparatus in the soft mass have no
drugs; what the drug does to the body palpably firm core. The process where in the
 Pharmacokinetics – study of the time large and solid particles are broken down to
course of drug movement in the body smaller or finer particles.
during the absorption, distribution, and  Dissolution - A process by which a chemical or
elimination; what the body does to the drug becomes dissolved in a solvent. Also
drug considered to be the rate-limiting step for
absorption.

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ø Rate-limiting step  The is because of the: First pass effect

- It is the slowest step in a series of kinetic  First pass effect (or Presystemic
processes. metabolism) - a phenomenon in which a
drug gets metabolized at a specific
Dosage forms in which Liberation is altered:
location in the body that results in a
 Parenteral (Intravenous (IV), Intramuscular reduced concentration of the active drug
(IM), Intradermal (ID), Subcutaneous (SC)) upon reaching its site of action or the
– bypass the liberation process because it systemic circulation
is already in a form of solutions already
Example: 100 mg Morphine  F = 0.25 or 25% -
 Per oral – no longer undergo disintegration means that 25 mg lang ang maabsorbed ng
ø sublingual tablets – intended to be
body natin at makakaabot sa ating bloodstream
dissolved under the tongue
or systemic circulation dahil nag undergo sa first
ø buccal tablets – intended to be
pass effect.
dissolved inside the cheek pouch
Distribution
Absorption
 It is the transfer of the drug from the blood to
 It is the process of uptake of the compound
extravascular fluids and tissues
from the site of administration into the
 The amount of blood perfusion in an area of
systemic circulation.
the body also affects the rate at which the
 Transfer of drug from the site of administration drug could be distributed there.
into the systemic circulation.
 Blood – main organ or principle organ for
 It is also the movement of the drug from the
distribution; responsible for the transport of
site of application to the bloodstream.
different substances all throughout our
 Main organ for drug absorption: small intestine
body and responsible for transporting our
 Dosage forms that bypass absorption:
drug molecules to the different tissues of
 Intracardiac Injection – the drugs are
our body, more specifically to transport our
directly injected to the heart or heart
drug molecules to its specific target tissue
muscle
or target site.
 Intravascular Injection – the drugs are
directly injected to the blood vessels Metabolism
ø 2 types of intravascular injection:
 Also known as Detoxification/Biotransformation
- Intravenous Injection – drug
 Refers to the process in which the drug
injected in veins
undergoes a chemical reaction in order to
- Intra-arterial Injection – drug
become more readily excretable.
injected into the arteries
 Simply the conversion of a drug molecule to
Bioavailability (F) its inactive form or more readily excretable
form (polar form).
 Bioavailability - A measurement of the rate
 Liver – main organ or principle organ for
and extent of systemic absorption of
drug metabolism
therapeutically active drug
 An Enzymatic or Biochemical transformation
 F = 1 or 100% - means that the drugs is
of the drug substance to (usually less toxic)
completely absorbed.
metabolic products, which may be
 Oral drugs - F < 1 (less than 1), hindi
eliminated more readily from the body
naaabsorbed completely or 100% of dose
 Metabolic products – metabolite
pag oral drugs
 Xenobiotics – foreign chemicals present in
our body

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Excretion Clinical Pharmacokinetics

 Final loss of the drug substance or its  Application of pharmacokinetic methods to
metabolites from the body drug therapy.
 Kidneys – major organ for excretion  The study of the relationships between drug
 polar metabolites through the kidney – dosage regimens and concentration–time
Renal Excretion; excreted via kidney, urine profiles
 non-polar drugs through the bile – Biliary  Dosage regimen – how much and how
Excretion; excreted through the bile, feces frequent, often a drug is administered or
 Renal Excretion – more common type of taken
excretion process; prerequisite = the  Dosage regimens 2 components: dose
metabolize drug product should be polar in and dose frequency
nature;  Dose – how much of the drug is
 Biliary Excretion administered
 Bile - digestive fluid produced and  Dose frequency – how frequent the drugs
secreted by the liver; that digestive fluid is is take or administered
used in order to break down fats; excreted  Concentration-time profiles – graph that
through feces shows the amount of drug present in the
 Biliary recycling –reabsorption of bile in the blood in a specific period of time.
small intestine
Three fundamental parameters:
Response
a. Clearance
 Refers to the therapeutic effect, - volume of fluid completely cleared of drug
subtherapeutic effect, side effect and toxic per unit time
effect of a drug. - unit: mL/min
 Refers to the direct measure of the - indicator of drug elimination
pharmacologic effect of a drug. b. Volume of distribution
 Therapeutic effect – means the drug is able to - apparent volume into which the drug has
produce a beneficial or favorable effect in distributed to produce the measured
which the expected therapeutic outcome is concentration
achieved. - Hypothetical amount/volume of fluid or
 Subtherapeutic effect – means the physiologic plasma that is necessary to dissolve a
effect of the drug is not enough to achieve certain dose or amount of drug in order to
the desired therapeutic outcome achieve or produce a certain plasma
 Side effect – refers to the other secondary concentration.
effects of the drug other than the desired or - unit: L
intended effect - used to quantify and describe the drug
 Finasteride – drug used for the treatment distribution process
of Benign prostatic hyperplasia (BPH) c. Elimination half life
 Beneficial side effect: promote hair growth - time taken for 50% of the drug to be
 Benign prostatic hyperplasia (BPH) – eliminated
condition that is very common in older - denoted as: t½
man wherein there is abnormal growth or - amount of time required to reduce/
increase in size of prostate eliminate the concentration of a drug by
 Alopecia – hair loss 50% or ½ of the dose of the drug
 Toxic effect – refers to the harmful effects - Ex. Paracetamol -> half-life = 2 hrs. (200 mg
produce by a drug, especially if the dose  after 2 hrs  100 mg.. and so on until ma
administered is too high or too excessive. eliminate ang drug from our body)

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TDM (Therapeutic Drug Monitoring) metabolism, and excretion characteristics of

a drug.
 Employed for very potent drug to optimize
 Pharmacokinetics experiments:
efficacy and to prevent any adverse toxicity
 In vivo – involves human subjects/
 Branch of clinical pharmacology that
laboratory animals; in Latin, means <within
specializes in the measurement of medication
the living=
levels in blood
 In vitro – employs test apparatus and
CPKS (Clinical Pharmacokinetic Service) equipment without involving human
subjects/ laboratory animals; in Latin,
 Provides pharmacokinetic and drug analysis means <in glass=
services for safe drug monitoring - Dissolution testing
 Referred to the different clinical services that
deal with pharmacokinetic and drug analysis Theoretical Pharmacokinetics
services for safe drug monitoring.
 Development of pharmacokinetics models
Therapeutic range that predict drug disposition after
administration
Drug mg/L  Branch of pharmacokinetics that focuses in
Digoxin (drug used to the prediction and calculation of plasma drug
0.5 - 2.1
treat heart failure) concentration after administration
Amiodarone 1.0 - 2.5
 Drug disposition – collective term for
Salicylate 150 - 300 distribution and elimination
Theophylline 10 - 20  Drug elimination – Metabolism and Excretion
Phenytoin 10 - 20
Carbamazepine 5.0 - 12 PHARMACOKINETICS: MODEL

Model – a hypothesis using mathematical terms

ø Potent drug – able to elicit or produce a to describe quantitative relationship concisely.
strong physiologic and therapeutic effect
ø Quantitative relationship between the
even at small doses.
plasma concentration and time
ø Therapeutic range – difference between the
minimum effective concentration (MEC) and a. Empirical – a model in which the plasma
the minimum toxic concentration (MTC) or concentration and time data are given an
maximum safe concentration. equation is derived from the given data
b. Physiological – describes drug movement in
Population Pharmacokinetics the body based or organ blood flow and
 Study of pharmacokinetics differences of organ spaces penetrated by the drug
drugs in various populations. c. Compartmentally based – a model in which
organs with the same blood flow and drug
Experimental Pharmacokinetics affinity are grouped together
 Development of biologic sampling Compartment Models - Hypothetical space
techniques, analytical methods for the bound by an unspecified membrane across
measurement of drugs and metabolites and which drugs are transferred
procedure that facilitates data collection and
manipulation. ø Refer to the hypothetical group of organs or
 Main goal is to established a pharmacokinetic tissues which have the same blood flow, drug
profile of a drug product affinity and drug distribution.
 Pharmacokinetic profile – comprehensive ø Used to describe drug distribution
description of the absorption, distribution,

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3 COMPARTMENT MODELS  Central compartment – group of tissues or

organs which have very high blood flow,
 Mamillary Model – One or more peripheral
blood perfusion and drug distribution.
compartments connected to a central
 Blood
compartment
 Brain
 Most common model used in clinical
 Liver
pharmacokinetics
 Central compartment: Represent plasma Catenary Model
and HIGHLY perfused tissues which
RAPIDLY equilibrate with the drug
 Catenary Model – Consists of compartments
joined to one another like the compartments
of a train
 Physiologic Pharmacokinetic Model (Flow
Model) – Considers that BLOOD FLOW is  Arranged in a series and follow a certain
responsible for distributing drugs to various sequence.
parts of the body  We do not use this in pharmacokinetic
Mamillary Model computation because it does not give an
accurate description of the actual drug
distribution in our body.

Physiologic Pharmacokinetic Model (Flow Model)

 Most comprehensive model

 Each organ or tissue are treated as a
separate compartment
 Blood flow limited – mas kokonti and supply
 Peripheral compartment – groups of tissues or ng blood
organs with similar blood flow, blood perfusion  Arterial blood – our drug molecules are
and drug distribution. However, the blood distributed to the different tissues via our
flow, blood perfusion and drug distribution arterial blood.
here is lesser compared to the central - Blood that is present in the arteries; it is
compartment. usually oxygenated blood.
 Rapidly equilibrating compartment –  Venous blood - drug molecules will dissociate
composed of tissues and organs where and leave the tissue through the venous
there is a high blood flow, high blood blood
perfusion and high rate of drug distribution. - Blood present in the veins that are usually
However it has lower values compared to unoxygenated blood.
central compartment
- Muscles
- Visceral tissues
 Slowly equilibrating compartment – group
of tissues and organs where there is a slow
blood flow, blood perfusion and slow rate
of drug distribution.
- Fats
- Bones

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Pharmacodynamics Importance of measuring plasma

drug concentration
 The study of the relation of the drug
concentration or amount at the site of action  Adjustment of the drug dosage in order to
and its pharmacologic response. individualize and optimize therapeutic drug
regimen
Clinical Toxicology
 Provides guide to the progress of disease state
 The study of the adverse effects of drugs and  Enable to modify the drug dosage
toxic substances in the body accordingly
 <All things are poison and nothing is without
Relationship between the drug, the drug product,
poison; only the dose makes a thing not a
and the pharmacologic effect
poison.= Stated by Paracelsus

Measurement of Drug Concentrations

 Sampling of biologic specimen

 Invasive Method
 Requires surgical/ parenteral intervention
 Sampling of blood, spinal fluid, synovial
fluid, tissue biopsy
 Non- invasive method
 Summary of LADMER process
 Without surgical/ parenteral intervention
 Feces, Urine, saliva Plasma Conc. Vs Time Curve

Blood
 Highly specialized tissue composed of many
different kinds of components
 Good indicator for drug absorption and drug
elimination
 Serum – no longer contain the clotting
proteins; does not contain fibrinogen.
 Plasma – anticoagulant: heparin
 Whole blood → clot → centrifuge →
supernatant → SERUM
 Whole blood → (+) heparin → centrifuge
→ supernatant → PLASMA  graph that shows the concentration of a drug
in the plasma after administration or over a
specific period of time
 x-axis: independent variable, time
 y-axis: dependent variable, plasma
concentration
 MEC (Minimum effective concentration)
- Needed to produce the desired
pharmacologic effect
- Minimum concentration needed to
produce the desired therapeutic or
pharmacologic effect, wherein if the drug
is below MEC, it only produces a
subtherapeutic effect.

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 MTC (Minimum Toxic concentration) or d. Rate of dissolution/ release of the drug

Maximum Safe Concentration from at the absorption site
- Needed to just barely produce toxic e. Delivery of drug to the site of action
effects
Biopharmaceutic Considerations in
- Minimum blood level at which our drug
Drug Product Design
starts to produce minimal toxic effect.
Above MTC: significant toxic effect  Therapeutic objective
 Therapeutic range  Drug (API)
- Difference between MTC and MEC, use as  Route of administration
index of safety, safe and effective (gaano  Drug dosage and dosage regimen
ka-safe ang product).  Type of drug product
 Narrow therapeutic range: smaller  Excipients
difference, hazardous drug product,  Method of manufacture
high probability of toxicity
 High therapeutic range: safe drugs, low  Drug Disposition – It is the description of drug
level chance to induce toxic or harmful distribution and elimination.
effect
 Onset time/ Onset of time PHYSICOCHEMICAL PROPERTIES
- Time required to reach MEC
- Needed for the plasma concentration of a. Drug Dissolution
the drug to reach MEC b. Drug Solubility
- indicator of onset of action c. Particle Size and Surface Area
 Peak time d. Partition Coefficient and Extent of Ionization
- time of Maximum drug concentration in e. Salt Formation
the plasma and a rough marker of f. Polymorphism
average rate of drug absorption g. Chirality
 Peak Concentration h. Hydrates
- Maximum drug concentration i. Complex Formation
 Duration of action
- Difference between the onset of time and A. Drug Dissolution
time for the drug to decline back to MEC  The rate at which the solid drug enters into
 AUC (Area Under the Curve) solution is often the rate limiting step in
- Amount of drug absorbed systematically bioavailability.
- Total area found under the plasma  The Noyes-Whitney equation describes the
concentration vs time curve from the initial diffusion controlled rate of drug dissolution
dose to final elimination of the drug from  The type and amount of excipients of drugs
the body can affect its solubility and dissolution rate.
BIOPHARMACEUTICS  Binders
 Biopharmaceutics: science which studies the
different factors that affect the drugs rate and
extent of absorption.

Involves factors that influence:  Lubricant: decreases the friction between

tablets/powders and metal surface;
a. Design of drug product
common excipients in tablets
b. Stability of drug within the drug product
c. Release of the drug from the drug product - very nonpolar and lipophilic
- Ex. Magnesium stearate

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D. Partition Coefficient and Extent of Ionization

 The partition coefficient of a drug is the ratio
of the solubility of the drug, at equilibrium, in a
non-aqueous solvent

 Disintegrant: promotes the rapid  the ratio of the solubility of the drug, at
breakdown of solid dosage forms equilibrium, in an aqueous solvent
 Determinant of lipophilicity or liposolubility
- If Partition Coefficient > 1, drug is
lipophilic (hydrophobic, non-polar)
- If Partition Coefficient < 1, drug is
hydrophilic (water-soluble, polar,
lipophobic)
B. Drug Solubility
 Increase in the number of carbon = non-
 In a saturated solution is a static (equilibrium) polar = lipophilic = high partition
property. The dissolution rate of a drug is a coefficient
dynamic property related to the rate of  Decrease water solubility = High partition
absorption. coefficient = high absorption
 maximum concentration of a substance that
can be completely dissolve in a given solvent
at a certain temperature and pressure
 "Like dissolves like"
 High polarity = high solubility in GIT = high
dissolution rate = low absorption (high polarity)

Figure 1
Water: aqueous layer, polar
Octanol: non-aqueous layer, non-polar

 Extent of Ionization
 Need both polar enough and nonpolar
enough  Drugs that are weak electrolytes (acids or
bases) exist in both an ionized form and a
C. Particle Size and Surface Area non-ionized form in solution.
 The extent of ionization depends on the
 inversely related
pKa of the weak electrolyte and the pH of
 As solid drug particle size decreases, particle
the solution.
surface area increases.
- pKa: negative logarithm of the acidity
 Low Particle Size = High Surface Area= High
dissociation constant, indicator or
Dissolution Rate (faster absorption)
measure of acidity of a substance
 The powders have high dissolution rate than
 The ionized form is POLAR , and therefore
the tablets
more Water soluble, than the non-ionized
 The pharmaceutical solutions have high
form
dissolution rate than the powders
- Ionized form: polar, water soluble,
hydrophilic, lipophobic
- Non-ionized form: non-polar,
liposoluble, lipophilic, hydrophobic

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- HIPE: Hydrophobic, Ionized, Polar,

WEAKLY ACIDIC DRUGS WEAKLY BASIC DRUGS
Excreted
- LUNA: Lipophilic, Un-ionized, Non-polar,  Hydrochloride
Absorbed (Diphenhydramine HCl)
 Sulfate (morphine
 Potassium (Losartan K)
sulfate)
 The Henderson-Hasselbalch Equation  Sodium salts
 Citrate
describes the relation between the ionized (Phenytoin Na, Na
 Gluconate salts
and the non-ionized forms of a drug as a Ascorbate)
 Estolate
function of pH and pKa  Napsylate
 pH = pKa →50% ionized and 50% unionized  Stearate salts

E. Salt Formation F. Polymorphism

 The choice of salt form for a drug depends on The ability of a drug to exist in more than
the desired physical, chemical, or one crystalline form
pharmacologic proper ties.  Amorphous, or non-crystalline, forms of a
drug have faster dissolution rates than do
 Example: Chloramphenicol
crystalline forms.
 Primary purpose: to increase the drug's water  Amorphous/ non-crystalline solid:
solubility, increase absorption rate irregular shape
 Drugs: weak acid + base = salt  Crystalline solid: definite structure and
 Drugs: weak base + acid = salt shape, particles are arranged in a
 Weakly acidic drugs: potassium and sodium pattern
salts Polymorphs
 Losartan Potassium - Same chemical structure
- Different physical properties: solubility, melting
 Phenytoin Sodium
point, x-ray diffraction (ability of a crystal to
 Sodium Ascorbate: sodium salt of ascorbic
scatter x-ray)
acid
 Example: cocoa butter, used as a
 Weakly basic drugs: hydrochloride, sulfate,
suppository base
citrate, gluconate salts, estolate, napsylate, - Alpha: melting point 22°C
and stearate salts - Beta prime: 28°C
 Diphenhydramine hydrochloric acid (HCl) - Beta stable: 34.5°C, used as a
 Morphine sulfate suppository base
 Dextromethorphan hydrobromic acid (HBr) - Gamma: 18°C
 Note: salts of long chain organic / fatty acids
G. Chirality
are non-polar (estolate, stearate, palmitate)
 Example: Chloramphenicol palmitate:  the ability of a drug to exist as optically active
antibacterial agent (see Figure 1) stereoisomers or enantiomers
o palmitate -> oral salt form  Enantiomers: non-superimposable mirror
o succinate -> more water-soluble salt images of a compound. Same chemical
(administered via IV) structure but different in orientation in 3
dimensional space
 Palmitic acid: 16 carbon carboxylic acid
 can express as "S" or "R", "levo" or "dextro"
 Individual enantiomers may not have the
same pharmacokinetic and
pharmacodynamic activity.

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 For example, ibuprofen (anti- inflammatory  For example: The chelate of tetracycline
drug) exists as the R- and S-enantiomers; only with calcium is less water soluble and is
the S-enantiomer is pharmacologically active. poorly absorbed.
 For example: Warfarin: anticoagulant R- - Tetracycline: broad spectrum
warfarin: longer half-life (t½), less distributed, antibiotic. It is capable of forming
less potent (weak); S-warfarin: shorter t½, complex or chelate with calcium.
more distributed, more potent

H. Hydrates

 Drugs may exist in a hydrated, or solvated,

form or as an anhydrous molecule
 Dissolution rates differ for hydrated and
anhydrous forms.
 Note: Anhydrous form is more soluble than
hydrated form
 Example:
- CuSO4: anhydrous form
- CuSO4•5H2O: hydrated form

I. Complex Formation

 A complex is a species formed by the

reversible or irreversible association of two or
more interacting molecules or ions.
 Chelates are complexes that typically involve
a ring-like structure formed by the interaction
between a partial ring of atoms and a metal
 complex in which a central metal ion binds to
a polydentate ligand
 Example: hemoglobin, insulin,
cyanocobalamin
 Complex formation usually alters the physical
and chemical characteristics of the drug.
 Large drug complexes, such as drug-protein
complexes, do not cross cell membranes
easily.

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TOPIC 2: Absorption and Distribution  Drugs with

ABSORPTION poor lipid
solubility
 The process of uptake of the compound from and
irritating
the site of administration into the systemic drugs
circulation. Easier to
 Covers a drug’s progress from the time it’s Intramuscular Rapid (aqueous inject than IV
administered, through its passage to the (IM) solution) Larger
Irritating drugs
Slow (non - volume may
tissues, until it becomes available for use by may be painful
aqueous be used
the body. solution) compared to
SC solution
Common Routes of Drug Administration Prompt from
Depends on
Subcutaneous aqueous solution
 Parenteral – involves the injection of the drug For insulin blood
(SC) Slow absorption
from repository injection flow and
directly to the body by passing the skin and injection volume
mucous membranes formulation
 Enteral – involves the absorption of the drug ENTERAL
via the gastrointestinal tract Not for most
Rapid abs from
 Transdermal – the drug product is topically Buccal or
lipid soluble
No < First drugs with
Sublingual Pass Effect= higher
applied on the skin wherein the drug drugs doses
penetrates the layers of the skin in order to Abs may vary > Some may
reach the systemic circulation Oral (PO) Slower Safest and have erratic abs
 Inhalation and Intranasal – the drug enters the absorption easiest route > First pass
oral or nasal cavity in order to reach the lungs compared to IV effect
> Supp may
and from the lungs the drug can also reach Rectal
For patient
migrate to
the systemic circulation. Abs may vary who cannot
different position
swallow
 Note: there are routes of administration in discomfort
which the absorption process is bypassed: OTHER
ø Bioavailability of Intracardiac, intravenous, > Easy to use
and intra-arterial routes = 1 or 100% Transdermal > Slow abs > Used for
> Irritation
 Intracardiac route – drug is directly > Inc abs with lipid-soluble
> Permeability
occlusive drugs with
injected to the heart (F=1) vary
dressing low dose and
 Intravenous route – drug is injected into the low MW
blood vessels (F=1) > Part. Size
 Intra-arterial route – drug is injected into Inhalation and determines
intranasal For local or anatomic
the artery (F=1)
Rapid abs systemic placement in
effects respiratory tract
Route Bioavailability Advantages Disadvantages
> Stimulate
PARENTERAL cough reflex

Intravenous Inc. chance of NOTES:

Immediate
bolus 100% Adverse
(IV bolus) effect
reaction  Intravenous bolus – refers to the single fast
 Plasma administration or rapid injection of medication
Intravenous drug levels Requires skill of into the veins.
infusion precisely insertion
(IV infusion) ø Administered at an angle of 25°
100 % controlled Tissue damage
 May inject at the site of ø Advantage: Capable of producing an
large fluid injection immediate therapeutic or physiologic
volumes effect

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ø Most of the emergency drugs are ø Maximum amount of drug solution that
formulated as intravenous bolus injection can be administered = 1.5 mL – 2 mL
ø Ex. Naloxone – antidote for opioid toxicity ø Administered at an angle of 45°
or poisoning; used in life threatening ø Ex of drugs administered via SC: Insulin,
situations Heparin
ø Disadvantage: increase probability of ø Bioavailability is the same with IM injection
increase risk of toxicity ø Advantage: the fatty tissue; adipose tissue;
 Intravenous infusion – refers to the gradual subcutaneous tissue can actually store
administration of a drug into the veins in which lipophilic drugs wherein they can act as
the drugs is usually administered at a storage depot or drug reservoir for the
controlled and constant rate. Mas malaking lipophilic drugs which are administered via
amount of fluid ang inaadminister dito. subcutaneous injection. These tissues can
ø Administered at an angle of 25° store the lipophilic drugs wherein they can
ø Ex. Parenteral nutrition, Electrolytes, anti- release it in a gradual and constant
cancer drugs manner. That can increase the duration of
ø Advantage: It is easier to adjust the plasma action of the drug.
concentration of the drug ø Disadvantage: only few drug solutions can
ø Preferred intravenous route if the drug is be administered. Only few blood supplies
irritating. received. Lesser blood supply  low rate
ø Disadvantage: can cause phlebitis of absorption
ø Phlebitis – <inflammation of the veins=  Intradermal injection – one of the most
 Intramuscular injections – the drug is directly common parenteral route of administration;
injected to the muscles the drugs is being injected into the dermis or
ø Administered at an angle of 90° inner layer of the skin
ø Ex. Vaccines and Hormones ø Administered at an angle of 10° - 15°
ø Common sites of injection: ø Usually used for allergy testing
- Deltoid muscle  Enteral routes of administration – the drugs are
- Gluteus muscle intended to be absorbed inside the
- Thigh muscles alimentary canal or gastrointestinal tract.
ø Bioavailability  Sublingual – intended to be dissolved under
- Aqueous solution – rapid absorption the tongue
process  Ex. Nitroglycerin – vasodilator that is used in
- Non-aqueous solution – slow the treatment of angina (a heart condition
absorption process that is characterized by an extreme pain
ø Easier to administer than intravenous because of decrease blood flow/supply in
injections heart)
ø It allows the administration of larger  Buccal – intended to be dissolved inside the
volumes of drug solution compared to cheek pouch
subcutaneous injections  Oral route - the most common and most
ø Maximum amount of drug solution that preferred route of administration; also
can be administered = 5 mL considered to be the safest, most convenient,
ø Disadvantage: painful and easiest route of administration.
 Subcutaneous injections – the drug is being ø Disadvantage: undergo first pass effect
injected into the hypodermis (the fatty layer  Rectal route – suitable route of administration
beneath the skin wherein it is mainly for patients who cannot swallow.
composed of adipose tissue) ø Preferred route if the drug is being
degraded by the gastric acid or intestinal

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enzymes; if the drug is sensitive to the The nature of the excipients

gastric acid or intestinal enzymes of our
 Binder
GIT.
 Disintegrant
 Transdermal route – active ingredients are
 Lubricants – non-polar in nature
delivered across the skin for systemic
Physical and chemical nature of the active drug
distribution
ø Transdermal patch – drugs which are  Particle size – faster dissolution process =
delivered via the transdermal route faster absorption process
 Ex. Nicotine patch – used by individual  Polymorphism – ability of a solid to exist in
who wants to quit smoking; reduce the more than one crystalline form
craving for cigarettes.  Solvates – hydrated or anhydrous form of a
ø Transdermal drugs have a very slow rate of drug
absorption, at the same time, their  Ionization – ration of the ionized and non-
absorption process can be increased by ionized form of a drug
the use of the occlusive dressing (medical
SYSTEMIC ABSORPTION OF
dressing in which it can prevent the
DRUG IS DEPENDENT ON:
escape of moisture from the skin)
ø Suitable route of administration for lipid  Physicochemical properties of the drug
soluble or lipophilic drugs with low dose  Surface area, solubility, Partition coefficient
and low molecular weight  Nature of the drug
 Inhalation and Intranasal – drug enters the  Anatomy and physiology of the drug
body via the nasal or oral cavity and the drug absorption
moves through the respiratory tract until it Types of Absorption
reaches the lungs.
 Transcellular - Process of drug movement
ø Ex. anti-asthma drugs
across the cell
ø Bioavailability: Very rapid absorption
 Paracellular - Process of drug movement that
process
goes through gaps or tight junction between
ø Local effects – physiologic or therapeutic
cell
effect of drugs is only contained in a
specific area
 Drug absorption requires the drugs to be
ø Systemic effects – scattered; drugs are
transported across various cell membranes
distributed to different tissues in the body
ø High dose of intranasal or inhalation drug =  Drug should be small and non-polar
produce a systemic effect
CELL MEMBRANE
ø Drugs absorption is limited by the particle
size of the drug  Also known as plasmalemma or plasma
membrane
PHARMACEUTIC FACTORS AFFECTING DRUG
 The outermost layer of a cell
BIOVAILABILITY
 A semipermeable structure composed
 the type of drug product (eg, solution, primarily of lipids and proteins
suspension, suppository)  Basic structural unit is phospholipid
 the nature of the excipients in the drug  Generally thin, approximately 70 to 100 A in
product thickness.
 the physicochemical properties of the drug ø 1 angstrom = 10-10 m or 0.1 nm
molecule  Molecules easily permeate or cross cell
membrane: small non-polar molecules

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 Primarily composed of: polar tails. Only allow the passage of non-
 Lipid polar or lipophilic molecules, and non-ionized
 Protein or hydrophobic molecules
 Major functions: ø Cholesterol – determines the rigidity or fluidity
 Hold together the aqueous cell contents of cell membrane
(structure) - More cholesterol = more rigid and stiff ang
 Separate cellular contents from the cell membrane
aqueous external fluid (barrier) - Less cholesterol = more fluid cell membrane
 Control transport of substances in and out ø Proteins
of the cell (regulation) a. Integral protein – embedded within the
phospholipid bilayer.
Theories of Cell membrane
Ex. protein channels
Lipid bilayer or unit membrane theory b. Peripheral protein – embedded on the
surface of the phospholipid bilayer.
 composed of two layers of phospholipids
Ex. receptors, cell surface markers
between two surface layers of proteins
 cell membranes have 2 phospholipid layers
and 2 protein layers

Parts of Cell Membrane

 Phospholipid
ø 1 polar head and 2 non-polar tails
- Polar head attract water: hydrophilic
Fluid mosaic model  3 components: phosphate, choline,
 consists of globular protein embedded in a glycerol
dynamic fluid, lipid bilayer matrix - Non-polar tails repel water: hydrophobic
 Proteins embedded in a phospholipid bilayer.  Made up of fatty acids or long carbon
 Called as fluid model because in this chain carboxylic acids
biological model the molecules are  Bilayer
constantly moving ø 2 layers of phospholipids
 Called mosaic because the cell membrane - The polar heads stay on the outside and
is composed of many and different kinds of the tails stay on the inside
small molecules
 Consists of globular protein embedded in a
dynamic fluid, lipid bilayer matrix

Important components

ø Phospholipid bilayer – composed of 2 layers

of phospholipid and many phospholipid
molecules. Phospholipid molecules are
composed of single polar head and 2 non-

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Cell Surface Proteins  Convective transport

 Ion Pair transport
a. Channel proteins - transport food and other
 Vesicular transport
molecules into the cell and transport wastes out
o Endocytosis
of the cells.
o Pinocytosis
ø Allows transport of hydrophilic substance and o Phagocytosis
small ions
TRANSPORT MECHANISM
ø Considered as an Integral protein
ø Ex. Na+ channel, K+ channel  Transport Mechanisms – moving material in
ø Ion channel protein – allow the passage of ion and out of the cell
across the cell membrane ø Active transport – utilize ATP; using/
b. Receptor proteins - gather information about requires energy
the cell’s surroundings ø Passive transport – do not utilize ATP; not
use/ require energy
ø Considered as peripheral proteins  Concentration gradient – the difference in
c. Cell surface markers - identify the type of cell, the amount of a substance inside and
important for cell recognition outside of the cell
1. Going <with the gradient= – high to low
ø Considered as peripheral proteins
concentration; passive
2. Going <against the gradient= – low
concentration to high concentration;
active
3. Equilibrium exists when the concentration
of molecules is the same throughout a
space (inside and outside the cell)
Permeability of the Cell Membrane
Passive Diffusion
1. Semi permeable/selectively permeable
 process by which molecules spontaneously
 Only certain substances can pass across the diffuse from a region of higher concentration
membrane. to a region of lower concentration
2. Factors that determine whether a molecule  Major transmembrane process for most drugs.
can pass through a membrane or not:  Major transport mechanism for small and non-
polar molecules
a. size – small molecular size/weight
ø Ex. Osmosis – passive diffusion of water
b. type (polar, non-polar) – can easily cross
across a permeable membrane.
cell membrane
 The passage of molecules through a
PASSAGE OF DRUGS ACROSS CELL MEMBRANE membrane which behaves inertly.
Absorption mechanism/ Transport mechanism  along the concentration gradient
 Absorption mechanism/ Transport mechanism  Fick’s first law - states that the rate of
ø Describes the process of how a drug diffusion is proportional to the difference
molecule moves in and out of a cell. in drug concentration on both sides of
 Passive transport the membrane
 Carrier Mediated Transport
o Active transport
o Facilitated transport

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1. D = diffusion coefficient of the drug through

the membrane (area/time)
a. Inversely proportional to molecule size; the
larger the molecular size, the lower the
diffusion coefficient which indicates a
slower rate of diffusion ø High rate of diffusion = High rate of absorption
b. Constant that measures the diffusivity Examples
which is the ability of a molecule to  Weak organic acids
diffuse through membranes
 Weak organic bases
2. A = surface area of the membrane through  Organic nonelectrolytes
which drug diffusion is taking place (area) ø Alcohol
a. Surface area of the cell membrane is ø Amidopyrine – analgesic
directly proportional to the rate of diffusion
ø Urea – waste product of protein
b. Larger surface area, faster rate of diffusion  Cardiac glycosides – drugs that increases the
3. Km/w = partition coefficient of the drug force of contraction of heart (ex. Digoxin)
between the lipoidal membrane and the
GI-fluids Carrier Mediated Transport
a. Partition coefficient – determinant of  Uses carrier/transport proteins
liposolubility that is also directly  Usually for polar and large molecules
proportional to the rate of diffusion
b. Higher partition coefficient, the more Characteristics of carrier mediated transport:
lipophilic molecule 1. Saturation – a limited number of carrier
c. More lipophilic, more non-polar, more binding sites are available.
non-ionized, higher partition coefficient 2. Selectivity – each carrier transports a specific
and faster rate of diffusion substance or a few closely related
4. h = thickness of cell membrane compounds
a. Inversely proportional to the rate of 3. Competition – several closely related
diffusion compounds may compete for transport on
b. Thicker, slow rate of diffusion the same carrier.
c. Thinner, fast rate of diffusion ø Compounds with similar structures may
5. Concentration gradient b/w GIT and compete for the same carrier protein
plasma – directly proportional to the rate of
diffusion Carrier mediated: Active Transport
a. Higher difference in drug concentration Characteristics
between GIT and plasma, faster rate of  carrier-mediated transmembrane process
diffusion  across the concentration gradient
b. To have a faster rate of diffusion, the  from regions of low drug concentrations to
concentration of drug in the GIT must regions of high concentrations
be higher compared to the drug of  an energy-consuming system; uses ATP
plasma

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 Fast process, faster than passive diffusion Carrier mediated: Facilitated Diffusion
 Plays an important role in the renal and biliary Characteristics
secretion of many drugs and metabolites.
 carrier-mediated transport system
 along concentration gradient
 moves from a region of high drug
concentration to a region of a low drug
concentration
 does not require energy
 saturable and structurally selective
 shows competition kinetics for drugs of a
similar structure

ø Na, K, I, hexoses, monosaccharides, amino

acids, strong organic acids and bases,
cardiac glycosides, pyrimidine bases,
testosterone, estradiol, 5-FU(5 fluorouracil), Fe,
Ca (Polar or large molecules/substances)
 Polar substances – Na, Ka, I, Fe, Ca
 Hexoses/Monosaccharides – glucose
 Amino acids – building block of proteins ;
polar functional groups
 Very similar to passive diffusion, they only differ
 Strong organic acids and bases
in the use of transport protein
 Cardiac glycosides – digoxin; can be
 Example: Vitamin B12 or cyanobalamin,
transported on either via passive
uptake of glucose by muscle and fat cells
diffusion or active transport mechanism
 Pyrimidine bases – organic bases present Notes
in genetic materials, nucleic acids, RNA or  Active Transport mechanism – absorption
DNA such as Cytosine ( present in DNA of glucose form the GIT
and RNA), Uracil (present in RNA),  Facilitated Diffusion – uptake of glucose by
Thymine (present in DNA) muscle and fat cells
 Testosterone/Estradiol – sex hormones;
non-polar but have large molecule size, Convective (Pore) Transport
therefore, they cannot easily cross the  Also known as paracellular transport
cell membrane via passive diffusion and  Movement of a compound across
their major transport mechanism would be membranes by way of passages between the
via active transport cells
 5-FU (5 fluorouracil) – polar anti-cancer;  Drug molecules dissolved in aqueous medium
structure is very similar to the structure of at the absorption site move along the solvent
pyrimidine base (Uracil) through the pore.
 Very small molecules and ions

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 Transport protein
ø may form an open channel across the lipid
membrane of the cell
 Drug transport across tight (narrow) junctions
between cells or transendothelial channels of
cells
 <Solvent drag= – the solvent or aqueous
medium which carries the dissolved molecules
into the pores or narrow junctions between
the cells
 Inner lining of pores may possess charges in
ø Example: Propanol (+) + Oleic acid (-) =
which if they have charges, they can attract
will form a neutral complex (non-polar
ions with opposite charges
molecule; can easily cross the cell
 Can also allow the transport of small ions membrane if non-polar)
especially if the ion has an opposite charge to
ø Examples
the charge of pore lining
 Quaternary ammonium compounds – R4N+
ø Examples
 Sulfonic acids – RSO3H
 Inorganic and organic electrolytes up to
150 to 400MW Vesicular Transport
 Ions of opposite charge of pore lining
 The process of engulfing particles or dissolved
 Ionized sulfonamides – a type of synthetic
materials by the cell.
antimicrobial agent
 Types of bulk transport which is a types of
transport in which it involves the transport of
large amount of substances or molecules.
 Transport of molecules in and out of the
cell by forming or using vesicles
ø Vesicles – cell organelles which are
described as tiny sacs that transports
material within or outside the cell

2 types of vesicular transport

ø Exocytosis – movement of molecules from

within the cell to the external environment
or extracellular fluid
ø Endocytosis – movement of molecules or
Ion Pair Transport
substances are from the external environment
 The absorption of some highly ionized or extracellular fluid into the cell
compounds at physiological pH cannot be - When it comes to drug absorption, we
explained by simple or passive diffusion or any are more concerned with the endocytosis
other existing hypothesis of absorption - The process of engulfing particles or
 Strong electrolytes drugs are highly ionized or dissolved materials by the cell
charged molecules, penetrate membranes  Pinocytosis – <cell drinking=; ingestion or
poorly engulfment of liquids by the cell

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 Phagocytosis – <cell eating=; ingestion Good for absorption

or engulfment of large solid particles by Not good as an absorption site - because intestines have a large
- because of shorter surface surface area because of the
the cell
area presence of finger hair-like
ø Endocytosis: projections.
ONLY transport mechanism that DOES NOT
ø Stomach is essential to absorption of a weakly
REQUIRE the drug to be in a solution
acidic drugs, theoretically weakly acidic
ø Examples: Endocytosis/Pinocytosis drugs they are better absorb in the stomach
 Fats, glycerin, starch while the weak basic drugs they are better
 Parasite eggs absorb in the small intestine.
 Vitamins A, D, E and K
 Plastic particles, hairs and yeast cells Review: How to know if a drug is a weak acid or
 Ferritin and insulin weak base given the salt form of the drug.
 Sabin polio vaccine
ø Weak acid – if the salt form ay meron sodium
- Sabin – oral or potassium or group 1 cation.
- Salk – administered via injection ø Weak base – kapag meron acid or meron
anion of acid in a salt form of drug. Ends with -
-amine or -ine.

1. Phenytoin Na – Weak acid

2. Phenobarbital Na – Weak acid
3. Digoxin K – weak acid
4. Naproxen Na – weak acid
5. Losartan K – weak acid
6. Dextromethorphan Hbr – Weak base
7. Cetirizine HCl – weak base
Anatomic and Physiologic 8. Quinine HCl – weak base
Considerations of drug absorption 9. Chlorpheniramine maleate- weak base
Comparison of the features of the stomach and
ø Maleate - an anion form of malic acid.
intestine in relation to drug absorption
 1,2,3,4 - best absorb in the stomach
 5,6,7,8- best absorb in small intestine
Stomach Intestine
 Basic - better absorb in small intestine
Essential for absorption of Essential organ for weakly basic  Acid - better absorb in stomach
weakly acidic drugs drugs
Basic (pH 6-8); depending on REMEMBER THIS!
Highly acidic Part (because of the excretion of
(pH 1.5-2) (pH 2-6) pancreatic juice which contain  Acidic drug + acidic environment = non-
bicarbonate ions) ionized
Covered with thick mucus layer Has villi, large surface area  Non-ionized or nonpolar- non-polar from
- (can act as physical barrier for - (villi – this are tiny hair, finger- of drug is considered to be more
absorption) like projections that line inside
- (kapag mas makapal mucus the small intestine) absorbable or readily absorbable form.
layer, mas bumabagal ang - (because of the presence of  Acidic drug + basic environment= ionized
formation or penetration drug in this villi, it increases the surface  Polar or ionized- less absorbable form
our GIT, mas mabagal na area ng ating small intestine.  Basic drug + basic environment= non-
rreach ang systemic circulation)
ionized
Short surface area Long  Basic drug + acidic environment= ionized

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LEARNING CHECK:  The most important site for drug absorption is

the small intestine.
What will happen to the absorption of aspirin
(acetylsalicylic acid- weakly acidic drug) if it is COMPONENTS OF TOTAL TRANSIT TIME
administered w/ NaHCO3 (antacid- makes (0.4 to 5 days)
gastric basic)?
 gastric emptying- 1.5 hours to 2hrs. Transport
 Acidic drug + basic environment = ionized of food and other substance from the
form= decrease absorption of the aspirin stomach into small intestine.
 Overdose or toxicity of aspirin- antidote is  small intestinal transit (3 to 4 hours; 7 hours)-
sodium bicarbonate injection passage of food and other substances inside
 Antacid- they can impair the absorption of our small intestines until to large intestines.
weakly acidic drugs.  colonic transit- passage of food and other
 Ionized form of the drug - readily excretable substances inside the large intestines until to
form rectum. 30-40 hours.
 HIPE- hydrophilic drug or ionized drug or
polar drug that would be the excretable 4 – 8 hours  fasting state (S and SI)
form of drugs 8 – 12 hours  fed state (S and SI)
 LUNA- lipophilic or unionized or non-ionized
Acidic drugs- advisable with meal because
and at the same time nonpolar that would
irritating to stomach
be the absorbable form of drug.
 Polar – more excretable Certain drugs usually take without meal to fast
 Non-polar- more absorbable absorption.

The major physiologic processes that occur in the Fed state

gastrointestinal system:  marami laman GIT. Increases transit time. Slow
movement of absorption
Secretion
 The transport of substances into the lumen of Fasting state
the gastro intestinal tract  empty GIT. Decreases the transit time. Fast
 includes the transport of fluid, electrolytes, movement of absorption
peptides, and proteins into the lumen of the
alimentary canal. Transit time
 the time it takes for food to pass through your
Digestion entire digestive tract
 Breakdown of food particles into the smaller
and simpler molecules. Digestive tract
 is the breakdown of food constituents into  also known as the gaseous intestinal tract.
smaller structures in preparation for
absorption.

Absorption
 Movement of substances form the
gastrointestinal tract to the bloodstream
 is the entry of constituents from the lumen of
the gut into the body. May be considered as
the net results of both lumen-to-blood and
blood-to-lumen transport movements.

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Notes  Very little drug dissolution occurs in the

esophagus
 Stomach- food particle are digested or
 Tablets and capsule that lodge in this area
broken down into simpler molecules
causing irritation
 Small intestines- undergo further digestion.
Considered as major absorption site for both Stomach
drug and foo particles.
 innervated by the vagus nerve also known as
 Large intestines - undigested and unabsorbed
substances they passed through LI until to cranial 10
reach rectum and they will be excreted to the  Fasting state - pH 2 to 6
rectum as diseases.  Fed state – pH 1.5 to 2
 Total transit time- time the food enters the  Contains gastric acid, which is made up of
cavity until the time in which the unabsorbed HCl, gastric acid secretion that is stimulated
by two hormones: Stomach acid secretion is
and undigested foods reach the rectum it is
called total transit time. stimulated by gastrin and histamine
- Histamine- naturally present in our body.
 Average total transit time 0.4 to 5 days.
Responsible for producing symptoms of
Different parts of GIT: allergic reaction. Antihistamine drugs:
Oral Cavity diphenhydramine, cetirizine. Histamine
stimulates gastric acid secretion. Ex: for
 Saliva
hyperacidity- class of drug that can give is
 main secretion; pH 7
histamine 2 blockers or h2 blockers. H2
 1500 ml/day
blockers are drug that ends with <-tidine=
 Enzyme in stomach (Ptyalin) – also known
such as cimetidine, ranitidine, famotidine,
as salivary amylase which digests starches
etc. H2 blockers they antagonized the
into simpler sugar molecules
action of histamine they prevent histamine
 Enzyme in stomach (Mucin) – acts as
form stimulating gastric acid secretion.
lubricant. It is glycoprotein present in both
- Primary purpose: to grind food and mix it
saliva and the mucus membrane of our
with acidic gastric acid
oral cavity.
- Antral milling- process of breaking down
Esophagus large food particles by the stomach and
passing them into small intestine
 connects the pharynx and the cardiac orifice - Empty stomach (fasting): 100 mL of gastric
of the stomach
fluid
 pH 5 – 6 - (fed) - >100 mL
ø esophageal sphincter - average capacity: about 1.1 to 1.2 L max.
 which prevents acid reflux from the 4L
stomach
 lower esophageal sphincter – valve 3 types of glands
between esophagus and stomach in
 Mucous glands- secrete gastric mucus.
which prevents the stomach content
Gastric mucus has 2 functions first is for the
from going back up to esophagus. If not
lubrication of the stomach in order to
function properly it can cause reflux of
facilitate the movement of food. Second it
gastric acid going to esophagus that
forms protective layer over the lining
can feel of burning sensation in chest
epithelium of the stomach cavity.
called heart burn.

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 Chief (zymogenic cells) - secrete inactive

enzyme pepsinogen. Pepsinogen is an
inactive enzyme that activate with the
presence of acid or low pH environment. Low
pH can activate pepsinogen converts it to
active enzyme which is pepsin. Pepsin
enzyme that is responsible for the breakdown
or digestion of proteins in the stomach.
 Parietal cell- secretion of HCl.

Stomach (additional notes)

Duodenum
 Gastrin release is regulated by stomach
distension and the presence of peptides and  Shortest portion of small intestines
amino acids  presence of proteolytic enzymes
 Stomach emptying influenced by the food  Amylase- carbohydrates
content and osmolality.  Pancreatic lipase
 High food content mas increase ang  Bile secretion (liver to duodenum): 250 – 1000
osmolality ng gastric fluid = increase of mL/day
gastric emptying time.  Pancreatic juice: 300 – 500 mL/day
 Digestive enzymes present in PJ such as
Small intestine amylase that responsible for breakdown
 Longer than to large intestine (1.5 meters) carbohydrates into simple sugar and also
 6 meters in length lipase that responsible for the breakdown
 pH 6 to 6.5 or digestion of lipids into fatty acids and
 Bicarbonate also trypsin responsible for breakdown of
 neutralizes the acidic chyme emptied proteins to peptide and from peptides to
from the stomach amino acids
 Chyme - mixture of partially digested
food and juices. JEJUNUM
 ester prodrugs are hydrolyzed  Middle part of small intestine
 they undergo metabolism they  Preferred IN VIVO drug absorption studies
converted to their pharmacologically (uses laboratory animals)
active form by the process of hydrolysis  Intestinal fluid: 3000 mL/day (average volume
 Presence of villi increase surface are that is secreted into the jejunum
 Large SA
** why Jejunum when it comes to IN VIVO drug
 Prodrugs – inactive drug that must undergo
absorption studies? Why not Duodenum?
chemical conversion/metabolism to become
pharmacologically active. - Because Duodenum is short

Parts of small intestine ** between Jejunum and Ileum, why Jejunum?

 Duodenum - most proximal part that - Because Jejunum has better absorption
connected to the stomach. site/characteristics compared to Ileum
 Jejunum - It is the middle portion
 Ileum - distal part. Terminal portion.

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ILEUM  Doesn’t need to pass through hepatic

 terminal part of the small intestine portal vein and liver
 Longest part of the small intestine  No first pass effect
 has fewer contractions than the duodenum.  High bioavailability of drug
 pH 7, with the distal part as high as 8
 Ileocecal valve – separates Small Intestine 3. Distal Rectum
from Large Intestine Vein present: Inferior Rectal Vein – it also drains
directly into the inferior vena cava
COLON
 lacks microvilli / does not contain villi or  Doesn’t need to pass through hepatic
microvilli portal vein and liver
 refers to large intestine  No first pass effect
 not good absorption site  High bioavailability of drug
 has lower surface area
 very limited in drug absorption due to the
more viscous and semisolid nature of the
lumen contents
 lined with mucin (lubricant and protectant)
 pH 5.5 to 7
 Drugs that are absorbed well in this region are
good candidates for an oral sustained-
release dosage form (gradual release of
active ingredients from the dosage form)
 The colon contains both aerobic and
anaerobic microorganisms that may
metabolize some drugs.

RECTUM
 15 cm, ending the anus
Drug absorption in the Gastrointestinal Tract
 Distal part of Large Intestine
 Drug absorption is variable/erratic  The most common transport mechanism
 The drug absorption in Rectum is highly for the absorption of drugs would be
dependent on the positioning or placement passive diffusion
of the drug within the rectum  Drugs may be absorbed by passive
diffusion from all parts of the alimentary
(3) THREE DIVISIONS OF RECTUM
canal including sublingual, buccal, GI, and
1. Upper Rectum rectal absorption.
 For most drugs, the optimum site for drug
Vein present: Superior Rectal Vein – it drains into absorption after oral administration is the
the hepatic portal vein upper portion of the small intestine or
 Drug passes through the liver, thus it duodenum region.
undergoes first pass effect, resulting the
lower bioavailability of a drug Gastrointestinal Motility
 GI motility tends to move the drug through the
2. Middle Rectum
alimentary canal so that it may not stay at the
Vein present: Middle Rectal Vein – it drains absorption site.
directly into the inferior vena cava  Refers to the contraction of the smooth
muscles of the Gastrointestinal tract

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 This is also a major factor that can affect the  Directly proportional to Absorption Rate (ú
rate and extent of absorption of a drug GER, úABSORPTION) then (ùGER,
ùABSORPTION)
The transit time of the drug in the GI tract
depends upon: ùGET, ú GER, ú ABS úGET, ùGER, ùABS
Fatty meal Cold foods
ø Pharmacologic properties of the drug Hot meal Mild exercise
ø Type of dosage form Stress Motility
ø Various physiologic factors Lying on the left Lying on the right
Side Side
 Physiologic movement of the drug within the Heavy exercise Standing position
Anti-motility
GI tract depends upon whether the
alimentary canal contains recently ingested
food or is in fasted or inter-digestive state.  Anti-motility drugs – drugs that decrease the
 fast GIT motility, fast movement of passage gastrointestinal motility by decreasing the
of drug in gastrointestinal tract contraction of the smooth muscles in GIT
 if may laman yung GIT, it results to slower
Examples of drugs that can decrease GIT Motility
GIT motility
and Rate and resulting slower Absorption Process
Gastric Emptying Time (GET)
Antidiarrheal drugs
 The time it takes the stomach to empty its - Diphenoxylate + Atropine (Lomotil)
contents - Loperamide (diatabs, Imodium)
 Major factor that affects the rate of Anticholinergics
absorption - Hyoscine butylbromide (buscopan)
 Duodenum --- has the greatest capacity Opiates
for the absorption of drugs from the GI - Morphine + Codeine
tract
 a delay in the gastric emptying time for *** HINDI PWEDENG PAGSABAYIN INUMIN YUNG
the drug to reach the duodenum will slow MGA DRUG NA YAN galet na qu emz
the rate and possibly the extent of drug Examples of drugs that can increase GER, reduce
absorption, hereby prolonging the onset GET and resulting Fast Absorption
time for the drugs.
(Motility enhancing drugs)
*** the longer it takes for the drug to reach the
duodenum, that would result to a slower rate of Antiemetic drugs
absorption of the drug - Metoclopramide
- Domperidone (Motilium)
*** If there is a delay in Gastric Emptying time,
that would also result to a delay in the drug Metoclopramide + Domperidone + other drugs =
absorption process increase rate of absorption of the other drugs

Gastric Emptying Rate (GER) Factors Affecting Gastric Emptying Rate

 refers to the rate at which the stomach 1. Volume of the stomach

transfers its contents into the duodenum or - ùVolume of the stomach, ù GER, úGET
small intestine 2. Type of meal – basta may food sa
 inversely proportional to Gastric Emptying stomach, it decreases GER and prolongs
Time. (úGER, ùGET,) GET
 Fatty acids – greatly decreases GER

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 Triglycerides – greatly decreases

GER
 Carbohydrates
 Amino acids
3. Osmotic Pressure
- amounts of solutes dissolved in gastric
fluid
- Decrease GER
- ùOsmotic pressure, úGER
4. Physical State of gastric content
- úParticle Size, ùGER, ùABSORPTION
5. Chemicals
- Acids - úGER (ùGET)
- Alkali (NaHCO3)
(ú conc. = ù GER, ùconc. = úGER)
6. Drugs
Anticholinergics úGER, ùGET, úABS
Narcotic analgesics
úGER, ùGET, úABS
(Opioids – morphine)
Metoclopramide
ùGER, úGET, ùABS
(Anti-emetic)
Ethanol úGER, ùGET, ùABS Intestinal Motility
7. Miscellaneous  Normal peristaltic movements mix the
Body Position contents of the duodenum, bringing the drug
- Standing Position = ùGER particles into intimate contact with the
- Lying right side = ùGER intestinal mucosal cells.
- Lying left side = úGER  The drugs must have a sufficient time at the
absorption site for the optimum absorption.
ø Viscosity = ùViscosity, úGER  For modified-release or controlled dosage
ø Emotional State = ex, stress úGER forms, which slowly release the drug over an
ø Bile salts = úGER extended period of time, the dosage form
ø Disease States = úGER must stay within a certain segment of the
ø Exercise = mild  ùGER, heavy  úGER intestinal tract so that the drug contents are
ø Gastric surgery = ex. Gastrectomy = ùGER released and absorbed prior to loss of the
<dumping syndrome= dosage form in the feces.
Example of Modified-Release Dosage Form
ø Diamicron XR (Gliclazide – antidiabetic)

** Modified-Release Drugs should not be

administered with motility enhancing drugs

ø Peristaltic movement/Peristalsis – refers to the

series of wave-like muscle contractions of the
smooth muscle of the gastrointestinal tract

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Effect of food on Gastrointestinal Drug Absorption

 The presence of food in the GI tract can
affect the bioavailability of the drug
 Digested food contains amino acids, fatty
acids, and many nutrients that may affect
intestinal pH and solubility of drugs.
 The absorption of some antibiotics is
decreased with food
 Griseofulvin – antifungal (better absorbed
when given with food containing a high fat
content)
 Mebendazole (anthelmintic)
 Fasted state = ùGER, ùABSORPTION
Perfusion of the Gastrointestinal Tract
 Enteric-coated tablets – Protects drug from
1. The Splanchnic circulation receives about 28% acidic pH, release in small intestine
of the cardiac output and is increased after Examples:
meals.  Bisacodyl (Laxative)
- irritating to the stomach
Splanchnic circulation – describes the blood flow
- should NOT BE taken with antacids –
to the abdominal gastrointestinal organs such as
premature release = gastric irritation
stomach, liver, spleen, pancreas, small and large
intestine

Mesenteric vessels supply.

2. The Lymphatic circulation in drug absorption is

well absorbed. Drugs are absorbed through the
lacteal or lymphatic vessels under the microvilli

 Bypasses the first-pass effect

 Important in the absorption of dietary lipids
 partially responsible for the absorption for
some lipophilic drugs
 INCREASED BIOAVAILABILITY

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Double-peak Phenomenon
 The double-peak phenomenon is generally
observed after the administration of a single
dose to fasted patients
 Food can also affect the integrity of the
dosage form causing an alteration in the
release rate of the drug
 The rationale for the double-peak
phenomenon has been attributed to
variability in stomach emptying, intestinal
motility, presence of food, enterohepatic
recycling, or failure of a tablet dosage form.
 Usually observed after the administration of a
single dose to a fasted patient

Examples of Drugs in Double-peek phenomenon:

Cimetidine + Ranitidine

Effect of Disease States on Drug Absorption:

ø Intestinal blood flow

ø Gastrointestinal motility
ø Changes in stomach emptying time
ø Gastric pH that affects drug solubility
ø Intestinal pH that affects the extent of
ionization
ø The permeability of the gut wall
ø Bile secretion
ø Digestive enzyme secretion
ø Alteration of normal GI flora

Drugs that Affect Absorption of Other Drugs

Anticholinergic Drugs ú rate of absorption

Metoclopramide (motility ù rate of absorption
enhancing drug) úextent of abs. of modified-
release drug
Antacids ú rate of absorption of acidic
drugs
Cholestyramine ú rate of absorption
Vitamin D ù absorption of calcium
Cholestyramine

 bile acid sequestrant. (promote

elimination/excretion of bile acids)
 Used as cholesterol lowering drug.
 Forms large complex with several drugs:
Thyroxine (thyroid hormone) and Digoxin
 Cholestyramine decreases the absorption of
thyroxine and digoxin

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TOPIC 3: Drug Elimination ANATOMY AND PHYSIOLOGY OF THE LIVER

Metabolism – Principles and Factors

 Also known as biotransformation

 The enzymatic or biochemical transformation
of the drug substance to (usually less toxic)
metabolic products, which may be
eliminated more readily from the body
 Enzyme – protein that catalyzes a chemical
reaction.
 Drug metabolism refers solely to the chemical
biotransformation of a drug by the biological
environment.
 In biochemistry, total amount of the
biochemical reactions involved in maintaining Liver
the living condition of the cells in an organism.
 Principal site of metabolism
Metabolism serves three principal purposes: - Hepatocytes – liver cells; contain
1. to supply energy for body functions and metabolizing enzymes
 Both synthesizing and eliminating organ
maintenance; Ex. glycolysis (metabolic
reaction)  Substances synthesized:
2. to break down ingested (foreign) compounds  Bile – produce in liver; greenish yellow fluid
and biosynthesis of more complex molecules; responsible for breaking down fats
Ex. ingested proteins (broken into simpler  Albumin – protein
molecules = amino acids, via metabolic  Cholesterol
reaction, they will be converted into more 1. Liver lobule - Basic unit of the liver
complex protein molecule)
3. To make compounds more polar water a. Larger right lobe
soluble; Ex. drug metabolism goal – convert b. Smaller left lobe
the drug molecule into a more excretable 2. Hepatic artery
form; (excretable from = more polar water
soluble form) a. Perfused blood in the liver
4. To inactivate the drug; inactivated drug – b. Carries oxygen in the liver
cannot cause of produce toxic effect
5. Detoxify harmful substances ø different from hepatic vein
6. To activate some drugs; there are drugs ø Hepatic vein – carries blood from the liver to
required chemical the heart
transformation/reaction/metabolism
3. Hepatic portal vein
ø Xenobiotics – foreign chemicals
a. Collects blood from the various segments
ø Drug metabolism is a preparatory process for
of the GIT that perfuse in the liver
excretion.
b. Carries nutrient to the liver
ø Prodrug – require initial metabolism before
being pharmacologically active 4. Sinusoids

a. Large vascular capillaries

b. Facilitates drug and nutrient removal
before the blood enters the general
circulation

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Metabolizing enzymes 3. METABOLITES WITH ALTERED ACTIVITY

 Present in hepatocytes or liver cells  There pharmacologic or therapeutic
 occur in the soluble, the mitochondrial, or activity is different from the original
the microsomal fractions drug/parent compound
 mitochondria – contain energy  Isotretinoin – Teratogenic drug (means
metabolizing enzymes toxic to the fetus; cannot be taken by
 microsome – contain drug pregnant)
metabolizing enzymes Examples:
 metabolism can also take place in the Iproniazid (Anti-depressant) → isoniazid (anti-TB molecule)
bloodstream to some extent because Retinoic acid (Vitamin A derivative) → Isotretinoin (anti-acne)
some enzymes produced by the cell spill
over into the extracellular fluid 4. BIOACTIVATED METABOLITE
 Metabolites of Prodrug
2 types of metabolism  Prontosil – a red organic dye; first prodrug
discovered by Gerhard Domagk
 Hepatic metabolism – metabolic process
Examples:
or reaction occurs inside the liver Enalapril → Enalaprilat (anti-hypertensive)
 Extrahepatic metabolism – metabolic Sulindac → active sulfide (anti-inflammatory)
process or reaction occurs outside the liver Levodopa → dopamine (anti-Parkinson drug)
Prontosil → sulphanilamide (antibacterial drug)
Metabolism
Hetacillin → ampicillin (antibacterial)
Metabolites – product of metabolic reaction Sulfasalazine → sulfapyridine {byproduct of the
ø Inactive metabolites aminosalicylic} + aminosalicylic acid {pharmacologically
ø Metabolites that retain similar activity active} (ulcerative colitis)
ø Metabolites with altered activity
ø Bioactivated metabolite 5. REACTIVE METABOLITE
ø Reactive metabolite  Toxic metabolites
 NAPQI – N-acetyl-p-benzoquinone imine
1. INACTIVE METABOLITES  Hepatotoxic metabolite
 They are no longer pharmacologically  Benzopyrene – aromatic hydrocarbon; Ex.
active, no longer capable of producing a
charcoal grilled food and cigarette
physiologic or therapeutic effect.  Malathion – an organophospahate
Examples:
insecticide
Procaine (local anesthetic) → p-aminobenzoic acid
6-mercaptopurine (immunosupressant) → 6-mercaptopuric acid
Examples:
amphetamine (CNS stimulant)→ phenylacetone Acetaminophen → NAPQI
phenobarbital (anticonvulsant)→ hydroxyphenobarbital Benzopyrene → Reactive epoxide metabolite (binds to DNA;
produced mutation that could develop cancer cells
2. METABOLITES THAT RETAIN SIMILAR ACTIVITY Malathion → parathion
 Retain the therapeutic or pharmacologic
activity of parent compound  Mostly, drug metabolites are more ionized
 Imipramine – also used for enuresis (bed- than their parent structures and are, therefore
wetting) in the form of water-soluble salts which have
Examples: reduced lipid solubility.
Imipramine (Anti-depressant) → desipramine
acetohexamide (antidiabetic) → L-hydroxyhexamide
Codeine (analgesic,antitussive) → Morphine
Procainamide (antiarryhtmic) → N-acetyl procainamide
phenylbutazone (anti-inflammatory) → oxyphenbutazone

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Three major components of a drug  Monooxygenase/mixed function oxidase

biotransformation enzyme – enzyme that introduce an oxygen
atom into a molecule
1. Reactant (drug or xenobiotics)
 Most common and most important class of
2. Product (metabolite)
enzymes for phase 1 metabolism
3. Reaction catalyst (enzymes)
 responsible for REDOX rxn
 Located primarily in the endoplasmic
reticulum of hepatocytes

PATHWAYS TO DRUG METABOLISM

Phase I Reaction

 Also known as functionalization phase or

unmasking phase
 Polar functional group: OH (alcohol func. grp),
SH (thiol func. grp), NH2 (amino func. grp)
 Non-synthetic
 Which small chemical changes occur in one
or more functional groups of drug
 3 types: Oxidation, reduction and hydrolysis
 CYP450 most important isoenzymes
a. Oxidation
responsible for liver metabolism.
b. Reduction
 CYP450 – 50+ types/variants of isoforms
c. Hydrolysis
 CYP3A4 – most common isoform
Phase II Reaction  Different type of cyp enzymes = different type
of drug being metabolized
 AKA Synthetic phase or conjugation phase
 A molecule provided by the body is added to Proportion of Drug Metabolized by P459 Enzymes
the drug
 Glucoronidation, sulfation, amino acid
conjugation, acetylation, glutathione
conjugation, methylation
a. Glucoronidation
b. Sulfate Conjugation
c. Methylation
d. Acetylation
e. Glutathione Conjugation
f. Amino Acid Conjugation

Phase 1 Metabolism

 Cytochrome P450 – class or family of enzymes

which are responsible for the phase 1
metabolism of drugs; most important enzyme
in phase 1 metabolism.

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Acetaminophen, Diazepam, Fluvoxamine,

CYP1A2 A. Ester hydrolysis (Procaine)
Theophylline, Methadone, Propranolol C. Hydrolysis Addition of H2O
B. Amide Hydrolysis (Lidocaine)
CYP2B1 Chlorpheniramine
CYP2B6 Bupropion, Cyclophosphamide
CYP2C8 Diclofenac, Omeprazole, Paclitaxel NOTES
CYP2C9 S-warfarin, Tolbutamide, Ibuprofen
S-mephenytoin, Cimetidine (hyper-acidity), A. Oxidation
CYP2C19  Most common oxidation reaction –
Fluoxetine
Antidepressants, Beta blockers (-olol) – hydroxylation reaction (insert –OH group or
CYP2D6
antihypertensive drugs, Captopril alcohol functional group)
Ethanol, Felbamate, GA (general  Deamination – removal of amino group;
CYP2E1
anesthetics), INH, ondansetron
product is a less polar metabolite
Acetaminophen, BZD (-zepam), Busulfan,
CYP3A4  Dealkylation – removal of an alkyl group
Amitriptylline, Amiodarone, Azole antifungals
(non-polar)
 Removal of non-polar mol.  less non-
FUNCTIONALIZATION PHASE polar metabolite (too produce a more
PHASE 1 ASYNTHETIC PHASE ADDING OR polar metabolite
UNMASKING FUNCTIONAL GROUP  Codeine – alkylation reaction it undergo is
 Aromatic hydroxylation O-demethylation (produce morphine)
(Phenytoin)  N-oxidation - paracetamol
 Aliphatic hydroxylation
(Phenobarbital) (acetaminophen) converted into NAPQI
 Olefenic hydroxylation  S-oxidation - sulfide functional group 
(Carbamazepine) sulfoxide (more polar functional group)
 Benzylic hydroxylation
 Desulfuration – thiono compound 
(Tolbutamide, Imipramine)
 Allylic hydroxylation carbonyl group (more polar)
(Pentazocine, Hexobarbital)  Dehalogenation – removal of halogen;
 Hydroxylation N-Alpha to a used to inactivate the drug
carbonyl (Diazepam,
Most dominant Dopamine)  Ethanol – 2 pathways: non CYP-450
phase 1  Oxidative Deamination mediated pathway (major pathway; using
A. Oxidation + O2 (increase) (Amphetamine) – inactivate special enzymes: alcohol dehydrogenase
- most common - H (decrease) drug and aldehyde dehydrogenase) and CYP-
reaction LEORA  N-dealkylation (Morphine,
Ephedrine) 450 mediated pathway (minor pathway;
 N-oxidation (Acetaminophen) phase 1 reaction/oxidation {CYP2E1})
 O-dealkylation (Codeine,  Acetaldehyde – toxic metabolite
Papaverine)
 S-dealkylation (6 –  Acetic acid – excretable metabolite
methylmercaptopurine)  Ethanoic acid; acetic acid – Carboxylic
 S-oxidation (Chlorpromazine) acids (one of the most functional group)
 Desulfuration (Thiopental)  Ethanol  acetaldehyde  acetic acid
 Dehalogenation (Halothane,
Chloramphenicol)
 Aldehyde dehydrogenase – affect alcohol
 Oxidation of alcohols (Ethanol, tolerance
Estradiol) B. Reduction
 Oxidation of aldehyde  Reduction – characterized by the
(Acetaldehyde, PGE2
A. Carbonyl reduction decreased in valence and gain of
+H (Acetohexamide) electrons; addition/increase of hydrogen
B. Reduction - O2 B. Azoreduction (Sulfasalazine) atom and removal/decrease of oxygen
GEROA C. Nitroreduction atoms
(Chloramphenicol)
 Oxidizing agents – substances that
undergo reduction

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 Carbonyl reduction – C=O  The faster elimination  decrease

 Type of compounds with carbonyl = of duration of action/ therapeutic
ketone (RC=OR) and aldehydes (RC=OH) effect
 undergo reduction, converted and  Amidases - enzymes responsible for
transform into an alcohol (more polar catalyzing amide hydrolysis reaction
compared to carbonyl containing (found only in the liver)
compounds)
Red Blood Cell (RBC) in metabolism
 Ex. Acetohexamide – anti-diabetic drug
 Azoreduction – refer to the reduction  Primary role is to transport or carry oxygen
reaction of Azo compound (RN=NR) molecules into the liver in which the oxygen
 RN=NR  RNH2(amine) + RNH2(amine) molecules are necessary for phase 1 reaction,
 Nitroreduction – chemical reaction in more specifically for redox reaction.
which the nitro functional group (RNO2) is  to exchange oxygen for carbon dioxide at
being reduced or converted to an amine the tissue level
 RNO2  RNH2(amine)  equipped with numerous enzyme systems
C. Hydrolysis (energy supply for the cell protection of
 Hydrolysis – reaction in which there is a hemoglobin and cell membrane from
breaking of chemical bond via the oxidation)
addition of water; common metabolic  has no nucleus, no mitochondria, no
pathway for local anesthetics ribosomes or m-RNA, it cannot synthesize
 Local anesthetics: Procaine and Lidocaine protein
 Ester hydrolysis  no cytochrome P-450
 Ester (RC=OOR) + H2O  Carboxylic
acid (RC=OOH) + alcohol (ROH){more PHASE 2 Reactions
polar products/substances}  AKA conjugation or synthetic reactions
 Ester local anesthetics (1i)  Conjugation or addition of a molecule from
 Procaine an endogenous substance to the parent
 Tetracaine compound
 Chlorprocaine  Enzyme: Transferase – a type of enzyme that
 Amide hydrolysis catalyze the transfer of group of atom from
 Amide local anesthetics like lidocaine one molecule to another
usually are secondary amide  Cofactor – pertain to the substances that are
(RC=ONHR) needed by certain enzymes to carry out
 Secondary amide (RC=ONHR) + H2O  catalysis of a particular chemical reaction.
Carboxylic acid (RC=OOH) + amine  Source of molecule that is to be
(RNH2) transferred to the parent compound or
 Amide local anesthetics (2i) drug
 Lidocaine
GLUCURONIC ACID CONJUGATION
 Bupivacaine
 Ropivacaine  Most common phase 2 reaction
 2 enzymes involved in hydrolysis:  AKA : Glucuronidation (major metabolic
 Esterases – enzymes responsible for pathway for adults)
catalyzing ester hydrolysis reaction;  is a condensation of the drug or its primary
found in the blood and other tissues of metabolite with d-glucuronic acid.
the body (more abundant); reason  The reaction requires activation of glucoronic
why ester local anesthetic have faster acid by synthesis of UDPGA (uridine
elimination rate or shorter t ½ diphosphate glucoronic acid)  cofactor.

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 Enzyme: Glucuronyl transferase or Glucuronides

Glucuronosyl transferase
 are more water-soluble than the parent
 UDPGA is formed from UDP-glucose by a
structures due to the large hydrophilic
dehydrogenase found in the supernatant
carbohydrate moiety; very polar
fraction of the liver.
 more acidic than the parent molecule
 The reaction between UDPGA and the drug is
hence are more ionized
catalyzed by glucuronyl transferase, a
 less easily permeate through membranes
solubilized microsomal enzyme found in the
and are poorly reabsorbed by the kidney
liver, kidney, GI tract and skin.
tubule
 Example of drugs: Acetaminophen
 Excreted in tubular secretion via kidneys,
(paracetamol), Morphine (narcotic
bile(minor)
analgesic), Diazepam (sedative hypnotic),
Chloramphenicol (antimicrobial agent)
 Microsomal drug inducers increase the
activity of glucuronyl transferase, whereas
microsomal enzyme inhibitors and some drugs
reduce or inhibit glucuronyl transferase
activity
 Enzyme inducers – stimulate or increase the
activity of metabolizing enzyme such as the
glucuronyl transferase = faster rate of
elimination of the drug
 Enzyme inhibitors – inhibit or decrease the
activity of enzyme such as glucuronyl
transferase = decrease rate of elimination of
drug

Condition wherein Glucuronidation is altered

ø During pregnancy
 glucoronidation is reduced probably due
to increase progesterone and
pregnanediol levels
 progesterone and pregnanediol levels –
considered as inhibitors of glucuronyl
transferase
 ú rate of elimination = ù plasma
concentration = ù risk of toxicity
ø Newborns
 very low glucuronyl transferase activity
 Gray baby syndrome
 kernicterus
 Glucuronide – metabolite or product of a
glucuronidation reaction Gray Baby Syndrome and Kernicterus
 Alcohols and phenols  ether type
glucuronides
 aromatic and aliphatic carboxylic acids 
ester type glucuronides

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 Gray baby syndrome – toxicity cause by Methylation

chloramphenicol; having an Ashen gray skin
 addition of methyl group (non-polar) to a
 Kernicterus – neurological disorder caused by
parent compound or drug molecule
hyperbilirubinemia; occurs when the
 minor pathway of metabolism
glucuronyl transferase is reduced or inhibited.
 of importance for many endogenous
 Hyperbilirubinemia – refers to a condition
substances (substances that are naturally
wherein there is an excessive levels of
occurring inside our body like
bilirubin in the blood
cathecolamines: Dopamine (chemical that
 Bilirubin – waste product of hemoglobin
mediates the sensation of pleasure in the
metabolism eliminated by our body via
brain; happy hormone) , Epinephrine and
glucuronidation; can cause brain
Norepinephrine (major neurotransmitters of
damage.
sympathetic nervous system; responsible for
 Drugs that compete for glucuronidation or
fight response); Histamine (substance
reduce the already low glucuronyl transferase
responsible for producing the symptoms of
activity can precipitate Kernicterus.
allergic reactions)
 Treatment: Administration of Phenobarbital to
 Enzyme: methyl transferase
the newborn or the mother before delivery
 S-adenosylmethionine (cofactor) is formed
 Phenobarbital – enzyme inducer; stimulate or
which reacts with the drug in the presence of
increase the activity of glucuronyl transferase
a methyl transferase
= increase of rate of metabolism/ elimination
 occur in different tissues, such as liver, brain,
chloramphenicol that cause gray baby
kidney, skin, blood cells, glands, nerve fibers
syndrome and rate of elimination of bilirubin
and lung
that cause kernicterus
 metabolite formed is less polar
 main purpose is to inactivate the drug

Acetylation

 does not make the drug polar

 main purpose is to inactivate the drug
 metabolic pathway for amines, amides, N-
containing compounds
Sulfate conjugation  addition of an acetyl group to a parent
 Addition of a sulfate molecule to a parent compound
compound/ drug  Acetyl – C=OCH3 (non-polar molecule) = less
 PAPS – cofactor polar metabolite
 Most common metabolic pathway for  Conjugation of aromatic primary amines,
newborns aliphatic amines, amino acids, hydrazines,
 Example of drugs undergo sulfation: hydrazides and sulfonamides
Acetaminophen (analgesic), Methyldopa  minor pathway of metabolism except for
(antihypertensive), Estrone (hormone) isoniazid and sulfonamides
 Enzyme: sulfotransferase or sulfokinase  Enzyme: N-acetyl transferase
 found in the liver, kidney and GI tract  Cofactor – Acetyl CoA
 limited and easily depleted  Important drug examples: (HIPS) – drugs
 with increasing drug doses sulfate caused drug induced Systemic Lupus
conjugation becomes easily saturated Erythematasus (SLE) – auto immune disorder in
which the immune system attacks the
different tissues of our body causing wide
spread inflammation and tissue damage.

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 Hydralazine (vasodilator)  Example of substances that are metabolized

 Isoniazid (anti-tubercular drug) via GSH conjugation: Naphthalene,
 Procainamide (local anesthetic and anti- Ethacrynic acid (diuretic drug), NAPQI (toxic
arrhythmic agent) metabolite)
 Sulfonamide (antimicrobial) ø A peptide of glutamyl- cysteine-glycine which
is important in the detoxification of reactive
 Expression of acetyl transferase is subject to
oxygen and is the main intracellular molecule
genetic polymorphism (variation in the
for protection of cell against electrophilic
expression of genes between populations)
compounds
 slow acetylators and fast acetylators
 Slow acetylators
 Ex. races: Egyptian, Caucasians,
African-American
 ú enzyme (N-acetyl transferase)  ú
rate of elimination (longer t ½)  ù
plasma concentration  ù risk of
toxicity
 High change of developed of drug
induced Systemic Lupus Erythematasus
after taking the HIPS
 Fast acetylators
 Ex. races: Asians, Eskimos
 ù enzyme (N-acetyl transferase)  ù
rate of elimination (shorter t ½)  ú
plasma concentration  ú effect
Metabolism of acetaminophen in Adults
 Genes – portions of DNA that codes for the
production of protein such as enzyme; gives ø Glucuronidation – major metabolic pathway
instruction to produce protein in the body for paracetamol or acetaminophen
 Newborns are not capable ø Via glucuronidation, it is being converted into
glucuronide metabolite (non-toxic, readily
Glutathione conjugation excretable)
 Addition of glutathione molecule to parent ø Sulfation – secondary metabolic pathway for
compound or drug molecule paracetamol acetaminophen
 Responsible for detoxification of free radical ø When paracetamol will undergo N-oxidation
or reactive oxygen species in Phase 1, it will produce toxic metabolite
 Glutathione – a peptide containing which is the NAPQI
glutamine, cysteine and glycine; very potent ø Glutathione – can neutralize NAPQI, can
reducing agent; thus, it can donate electron convert it to a non-toxic glutathione
to free radicals metabolite
 Free radicals – molecules that have an ø Maximum daily dose of paracetamol: 4g (8
unpaired electron; highly reactive 500 mg paracetamol tablets)
 Reactive oxygen – example: hydroxyl radical
Metabolism of acetaminophen in
 Enzyme: Glutathione S transferase Infants/Newborns
 Cofactor: Glutathione
 Has a synergistic effect with vitamin C ø Sulfation – major metabolic pathway for
 + vitamin C – also a reducing paracetamol in pregnant woman and
agent/antioxidant newborns

PHBP221 35
Biopharmaceutics and Pharmacokinetics
1ST SEMESTER – PRELIM

Amino acid conjugation Glutamine conjugation

 Addition of amino acid molecule to a parent  for conjugation with organic acids such as
compound or drug molecule phenylacetic and related acids
 Important metabolic pathway for organic  Enzyme: N- Acyltransferase
acids such as salicylic acid and nicotinic acid  Cofactor: Coenzyme A (Acyl CoA)
 Enzyme: N- Acyltransferase
Maturation of Metabolic Processes in infant
 Cofactor: Acyl CoA
ø Glycine conjugation – amino acid added AGE Metabolism Capacity Developed
or transfer to parent molecule is glycine Birth Sulfation
ø Glutamine conjugation – amino acid 1st week Reduction, Oxidation
added or transfer to parent molecule is 1 month Acetylation
glutamine 2 months Glucuronidation
Glycine conjugation
Glutathione conjugation
3 months
Cysteine conjugation
+ N-Acyltransferase is developed

Enzyme Induction

 Drug or chemical-stimulated increase in

enzyme activity
 Alteration in the enzyme activity in liver
microsomes resulting in a faster rate of
metabolism
 not a disease; it is an adaptation of the body
to exogenous material
 ù enzymes ù metabolism ú effect
 ù activity of enzymes = ù rate of
Glycine conjugation metabolism/elimination (shorter half-life) = ú
plasma concentration = ú intensity and
 Most common endogenous amine for
duration of pharmacologic effect
conjugation with organic acids (aromatic
 Nababawasan ang effectiveness ng drug
heterocyclic carboxylic acid drugs and
dahil naeeliminate agad
aliphatic acids)
 Bile acids are conjugated with glycine Auto-induction
 Limited
 Enzyme: N- Acyltransferase  A drug that stimulates its own metabolism
 Cofactor: Coenzyme A (Acyl CoA)  EX. Phenobarbital is given repeatedly its
 Reduced in liver damage metabolism is increased
 Reduced in newborn and aged Foreign-induction
 Benzoic acid  hippuric acid
 one enzyme inducer stimulate the rate of
metabolism of another drug
 EX. If a dose of hexobarbital is then given its
metabolism is also increased
 Hexobarbital induces the metabolism of
phenobarbital

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Biopharmaceutics and Pharmacokinetics
1ST SEMESTER – PRELIM

Enzyme Inducers grapefruit juice; chemical that has anti-

oxidant and anti-inflammatory properties
 Increase the rate of metabolism of other drug
= decrease plasma concentration = decrease  Decrease the efficacy of prodrugs – efficiency
effect is increase by enzyme inducers.

ø P- Phenytoin First pass effect

ø P- Phenobarbital
 Aka: PRESYSTEMIC METABOLISM
ø R- Rifampicin
 initial BIOTRANSFORMATION of an active drug
ø C- Carbamazepine (auto-induction) –
BEFORE reaching the systemic circulation
example of a drug that shows extensive
 reduces the systemic availability of the drug
auto-induction
 IV and PO
ø C- Cigarette smoking – contain polycyclic
 eg. Propranolol (anti-hypertensive drug), NTG
aromatic hydrocarbons (substances that
- nitroglycerin (vasodilator), Morphine
acts as enzyme inducers)
(narcotic analgesics), Pentazocine (narcotic
ø C – Chronic alcoholism – refers to alcohol
analgesics), meperidine (narcotic analgesics),
consumption for a long period of time;
Verapamil (anti-arrhythmic drug)
enzyme induction; Acute alcoholism –
 NTG: Oral BA: <1; If sublingual, increase BA
enzyme inhibition.
Learning Check!
Enzyme Inhibition
1. Ms. Danvers takes Phenytoin as a
 May be due to substrate competition o due
maintenance drug for her epilepsy. She was
to direct inhibition of drug metabolizing
recently diagnosed with tuberculosis and she
enzyme
was prescribed with Isoniazid. After several
 ú enzymes ú metabolism ù effect
days of taking Isoniazid, she had experienced
 decrease enzyme activity = decrease rate of
ataxia and slurred speech which is neurotoxic
elimination (increase half-life (t ½)) = increase
effects of Phenytoin. How can you explain this
plasma concentration = increase
phenomenon?
pharmacologic effect = increase risk of
toxicity ø Isoniazid is an enzyme inhibitor
ø Isoniazid inhibited the metabolism or
Enzyme Inhibitors
elimination of phenytoin and thus, resulting to
 decreases the rate of elimination of other an increase in the plasma concentration on
drugs. phenytoin.
 Because of decreased elimination,
ø M- Metronidazole (anti-microbial)
phenytoin plasma level might have
ø E- Erythromycin (anti-bacterial)
exceeded the minimum toxic
ø D- Disulfiram (used to treat alcoholism)
concentration and thus, had toxic effects
ø I- Isoniazid (anti-TB drug)
like ataxia and allured speech.
ø C- Cimetidine (histamine antagonist used in
the treatment of hyperacidity); very potent 2. Katya is sexually active woman who takes oral
enzyme inhibitor; not to be used with other contraceptives on a daily basis. She was
drugs) diagnosed with epilepsy and was prescribed
ø K- Ketoconazole (anti-fungal drug) with Phenobarbital. After 2 months, she had a
ø V- Valproic acid (used to treat seizures) positive result for pregnancy test. She was
ø A- Acute alcoholism confused about thus as she never missed a
ø G- Grapefruit juice (Naringin) – compound dose of her oral contraceptive drug. How can
with enzyme inhibitory action present: you explain this case?
furocoumarins; Naringin – component of

PHBP221 37
Biopharmaceutics and Pharmacokinetics
1ST SEMESTER – PRELIM

ø Phenobarbital is an enzyme inducer.

ø Phenobarbital induced the metabolism/
elimination of the oral contraceptive drug,
resulting to a decreased plasma
concentration of the oral contraceptive.
ø ú plasma concentration of oral
contraceptive = ú effectiveness

Excretion

 the final LOSS of the drug substance or its

metabolites from the body such as through Regulation of Renal Blood flow
the kidney (urine), intestines (feces), skin
(sweat), saliva, and/or milk. ø Blood flow to an organ is directly proportional
to the arteriovenous pressure difference
Drug Elimination (perfusion pressure) across the vascular bed
 Irreversible removal of drug from the body by and indirectly proportional to the vascular
all routes of elimination. resistance.
 Collective term for metabolism and excretion Nephrons / malphigian bodies
Nonvolatile drugs ø responsible for the removal of metabolic
 are excreted mainly by renal excretion, into waste and the maintenance of water and
the urine electrolyte balance

Volatile drugs Parts

 gaseous anesthetics, or drugs with high  Capillary part

volatility, are excreted via the lungs into  Glomerulus
expired air  Bowman’s capsule

Clearance Tubular part

 the process of drug elimination from the body  PCT

or from a single organ without identifying the  LOH
individual processes involved.  DCT
 the volume of fluid cleared of drug from the  CD
body per unit of time  Ureter
 mL/min or L/hr.

Kidney

 Located in the peritoneal cavity

 most important organ for excretion
 maintain normal fluid volume
 maintain salt and water balance
 with 2 endocrine fxn
 secretion of renin(regulates BP)
 secretion of erythropoetin(RBC production)

PHBP221 38
Biopharmaceutics and Pharmacokinetics
1ST SEMESTER – PRELIM

3 kidney processes  Diet rich in:

 Carbohydrate  higher urinary pH
1. Glomerular filtration
 protein  lower urinary pH
2. Active tubular secretion
 Drugs (ascorbic acid and antacids)
3. Tubular reabsorption
 alter urinary pH when administered in large
Glomerular Filtration quantity
 Intravenous fluids (solutions of bicarbonate or
 filtration of LMW molecules (MW<500) ammonium chloride)
 normal GFR:125mL/min (180 L/day)
 change urinary pH and alter drug
 GFR - tells how healthy the kidney is reabsorption
 ave urine: 1-1.5 L(99% are reabsorbed)
 depends on pressure Drug Clearance
 100 mmHg - pressure of artery
 pharmacokinetic term for describing drug
 45-65 mmHg - pressure on glomerulus
elimination from the body without identifying
Active renal secretion the mechanism of the process
 described in terms of volume of fluid clear of
 Occurs in proximal Convuluted tubule drug per time unit
 Reabsorption of water and active secretion of  fixed volume of fluid (containing the drug)
some weak electrolyte ( weak acids) cleared of drug per unit of time
 Requires carrier and energy ( against conc  units : volume/time (eg, mL/min, L/hr)
gradient)
 reflects the effective renal plasma flow (ERPF) Organ clearance
- 425 to 650 mL/min
1. Renal clearance - voL of plasma that is
 Drugs used to measure active tubular
cleared of drug per unit time through the
secretion
KIDNEY
 P-amino hippuric acid (PAH) and
2. Hepatic clearance - voL of plasma that is
iodopyracet (Diodrast)
cleared of drug per unit time through the
 These substances are both filtered by the
LIVER
glomeruli and secreted by the tubular cells
3. Creatine clearance - ratio of creatine in the
Tubular reabsorption urine and creatinine in the plasma

 occurs in Distal convoluted Tubule

 If a drug completely reabsorbed (eg.
Response
Glucose), then the values for the clearance of
the drug is approximately zero.  refers to the therapeutic effect, sub-
 For drugs that are partially reabsorbed, therapeutic effect, side effect and toxic
clearance values will be less than the GFR of effect
125 to 130 mL/min
 Reabsorption of water and passive excretion
of lipid soluble drugs
 Depends on urine pH
 Based of Henderson-Hasselbalch equation

 Acidic Urine + Acidic Drug = Reabsorb

 Acidic urine + Basic Drug = Excreted
 Basic urine + Acidic drug = Excreted
 Basic urine + Basic drug = Reabsorb

PHBP221 39