Basra University college

of science and Technology

Introduction to Biopharmaceutics
Lecture No. 1

Presented
Farouk M. Sakr
Prof. of Pharmaceutics
PhD London University
Basic Terms
➢ Drug:
A chemical substance used in the treatment, cure, prevention, or diagnosis of disease/ disorder
➢ Dosage forms:
Means by which drug molecules are delivered to sites of action within the body
➢ Dose:
It is the quantity of drug taken or given e.g. 25 mg, 5 ml, 250 mg/ml
➢ Dosage Regimen:
Gives the name and the quantity or concentration of drug with frequency of schedule of
administration e.g. Diazepam 6 mg per day in 3 divided doses
➢Pharmaceutics:
Deals with physicochemical properties of drugs and their dosage forms
(tablets, capsules, emulsions, suspensions, ointments, creams….etc.)
➢Biopharmaceutics:
Defined as the study of how
• the physicochemical properties of drugs,
• dosage forms and
• routes of administration affect the rate and extent of drug absorption
➢Bioavailability:
Defined as the rate (how fast mg/min) and extent (how much of drug
mg/g)) absorbed from the dose into the blood.
• Example: 500 mg dose paracetamol 450 mg in the blood
➢Pharmacokinetics: (effect of the body on the drug)
Defined as the study of time course (time required) for drug ADME (absorption,
distribution, metabolism, excretion) and their relationship with its therapeutic and
toxic effects of the drug
➢Clinical pharmacokinetics:
The use of pharmacokinetic principles in optimising the drug dosage to suit
individual patient needs and achieving maximum therapeutic effect.
➢Pharmacodynamics: (effect of the drug on the body)
Defined as the study of the pharmacological, therapeutic and toxic effects of the
drugs on the body.
Summary
ADME PROCESSES
ADME PROCESSES
 ABSORPTION PHASE
oIf a drug is given intravenously (IV), it is administered directly into the blood,
and therefore we can be sure that all the drug reaches the systemic circulation.
The drug is therefore said to be 100% bioavailable.
o All other routes of administration where a systemic action is required, involve
the absorption of the drug into the blood.
A typical blood plasma concentration-time curve obtained following the peroral
administration of a single dose of a drug in a tablet
C max: the highest plasma drug concentration observed.
T max: the time at which C max occurs following administration of an extravascular
dose.
AUC: Area under the curve
MSC: Maximum safe concentration
MEC: Minimum effective concentration
Therapeutic range: The range of plasma concentrations between the minimally
effective concentration and the maximum safe concentration
Absorption phase: Absorption rate > Elimination rate
Elimination phase: Elimination rate > Absorption rate
The rate and extent of drug absorption
 Passage of Drugs Across Membranes
• The membrane can be viewed as a semipermeable lipoidal sieve that allows the
passage of: -
• lipid-soluble molecules across it by passive lipid diffusion
• water and small hydrophilic molecules through its numerous aqueous pores.
• other molecules by transporter proteins or carrier molecules that exist in the
membrane (e.g., facilitated transport)
 Various methods of membrane transport (Absorption)
➢Movement of drug from site of administration into blood circulation through
cell membrane
Oral dose – mouth - stomach – Intestine membrane – absorption - blood
circulation
i. Passive diffusion (Transport)
ii. Facilitated diffusion (Transport)
iii. Active Transport
iv. Pore Transport
v. Ion-pair Transport
vi. Endocytosis
 Passive Transport (absorption)

Concentration Gradient

Drug at higher conc. (GIT) Drug at lower conc. (Blood)

It depends on concentration gradients (i.e., difference between higher and lower
concentration).

90% of drug absorption occurs by passive transport (absorption)

 Facilitated Transport (absorption)

Drug moves from higher concentration to lower concentration

BUT with the help of carrier bodies (proteins)
Carrier Bodies (Proteins)

Drug at higher conc. (GIT) Drug at lower conc. (Blood)

 Active Transport (absorption)

➢Drug moves against concentration gradients (i.e., from lower concentration to

higher concentration)
BUT with the help of ATP (ENERGY)

ATP (ENERGY)

Drug at lower conc. Drug at higher conc. (Blood)

 Paracellular and Transcellular Transport
❖Two pathways exist for the passage of water and electrolytes across the
intestinal mucosa, transcellular and paracellular.
❖The transcellular pathway allows the passage of hydrophilic molecules of low
molecular weight and with small molecular size through the water filled pores
in the cell membranes. Example: ranitidine , acyclovir.
❖The paracellular pathway allows access of larger molecules through the
junction between the cells.
 Pore Transport

In this method, only

low molecular size and low molecular weight water soluble drugs can pass
through small pores present in membranes.
 Ion Pair Transport
oIt involves absorption of ionic drugs which have positive / negative charges
oStrong electrolyte drugs are highly ionized and maintain their charge at
physiological pH.
• These drugs penetrate membranes poorly, WHY?
oWhen linked up with an oppositely charged ion,
an ion pair is formed in which the overall charge
of the pair is neutral.
The neutral complex diffuses more easily across
the membrane, WHY?
❑propranolol, a basic drugs that forms an ion pair with oleic acid
 Endocytosis and Exocytosis
oIn this method drug with large size are transported via engulfment by the cell
membranes.
o This large size can’t cross cell membrane easily
Two types of Endocytosis
a. Phagocytosis (engulfing larger size molecules)
Cell eating
o This process is important in the absorption of
polio and other vaccines from the GIT.
b. Pinocytosis (engulfing smaller size molecules)
Cell drinking
o involves the ingestion of fluids or dissolved
particles.
o Fat soluble vitamins A, D, E and K are absorbed via pinocytosis
Summary of important transport process and drug absorbed through them

Absorption Mechanism Drug Absorbed

Passive Diffusion Most drugs having lipophilicity and MW between 100-400

Pore Transport Water soluble drugs of MW less than 100

Ion-pair Transport Drugs that ionise at all pH conditions absorbed after complexing
with oppositely charged indigenous ions

Carrier mediated Structure-specific drugs with affinity for carriers transported from
Transport specific sites

Endocytosis Macromolecular nutrients and drugs as solid particles or oily

droplets
 Factors Affecting Drug Absorption
o Factors Related to Drug:-
i. Lipid-water solubility
a. Lipid soluble increase absorption (cell membrane is lipophilic in nature)
b. Water soluble decrease absorption
ii. Particle size
a. Increase particle size decrease dissolution & absorption
iii. Ionization
a. Unionized drug is lipid soluble increase absorption
b. Ionized drug is water soluble decrease absorption
 Factors Affecting Drug Absorption
➢Factors Related to Drug (continue):-
iv. Concentration of drug
a. Higher concentration produces higher absorption
v. Drug solubility
a. Higher solubility produces higher absorption
vi. Dissolution rate
a. High dissolution produces higher solubility
vii. pH of drug
a. a. Acidic drugs absorbed in stomach e.g., Aspirin
b. b. Basic drugs absorbed in intestine e.g., Diazepam
 Effect of Dissolution on Drug Absorption
• How does dissolution affect drug absorption?
• Solid drug must dissolve before absorption can occur,
• dissolution rate determines availability of the drug for absorption.
• Dissolution, if slower than absorption, becomes the rate-limiting step for drug
absorption.
 Factors Affect Dissolution Rate and Drug Absorption
• The rate of dissolution depends on:-
oParticle size (smaller the particles the larger the SA the higher dissolution)
o Nature of solute and solvent
o Temperature
o Degree of saturation (high saturation decrease dissolution)
o Presence of mixing (mixing increase dissolution rate)
o Interfacial surface area (reduced particle size increase surface area)
o Presence of inhibitors (substance adsorbed on the surface as coatings)
 Effect of Dissolution on Drug Absorption

➢ The Diffusion Layer model/ Film Theory:-

It involve Two steps:-
a. Solution of the solid to form stagnant film or diffusion layer which is
saturated with drug.
b. Diffusion of the dissolved solute from the stagnant layer to the bulk of
solution.
Effect of Dissolution on Drug Absorption
 Effect of Dissolution on Drug Absorption

➢ The rate of dissolution is given by …….

Noyes and Whitney equation
𝑑𝐶 𝐷𝐴 𝐾𝑤/𝑜(𝐶𝑠 − 𝐶𝑏)
=
𝑑𝑡 𝑉ℎ
D = diffusion coefficient of drug
A. = surface area of dissolving solid
Kw/o = water/oil partition coefficient of drug
V = volume of dissolution medium
h. Thickness of stagnant layer
(Cs – Cb) = concentration gradient for diffusion of drug
 Effect of Dissolution on Drug Absorption

o order dissolution rate process depend on concentration gradients.

o This is true for in-vitro dissolution which is characterized by non-sink
conditions.
o The in-vivo dissolution is rapid as sink condition is maintained by absorption
of drug in systemic circulation
o i.e., Cp = 0 and rate of dissolution is maximum.
 Factors Affecting Drug Absorption
o Factors Related to Body:-
i. Surface area of absorption site
a. Higher surface area increase absorption
ii. Age
a. Drug absorption increased in adults compared to children and elderly persons
iii. Vascularity (number of veins)
a. Higher blood supply produces higher absorption
iv. Food type and contents
a. Affect drug absorption increase or decrease
v. Disease condition
a. Some disease like gastric ulcer, constipation and low gastric HCl (Achlorhydria)
 GIT Physiology and Drug Absorption
Gastric emptying time and motility:-
- Rapid stomach emptying increase bioavailability
o Effect of food on drug absorption:-
- Fatty food increase absorption of lipid soluble drugs
- Bulky food retard drug absorption and bioavailability
o Enterohepatic circulation:-
- Increase drug bioavailability
- prolong duration of action
- need dose adjustment (to avoid drug accumulation)
oFirst pass effect:-
- for oral administration cause decrease in bioavailability
 Routes of Drug Administration
oDetermines the site of application of the drug product.
oOften the goal is to attain a therapeutic drug concentration in plasma from
which drug enters the tissue (therapeutic window between toxic concentration
and minimal effective concentration)
Routes of administration are classified into

ENTERAL and PARENTERAL

o Enteral means through the GI tract and includes oral, buccal, and rectal.
oParenteral means not through the alimentary canal and commonly refers to
injections such as IV, IM, and SC; but could also include topical and inhalation
 A. Enteral Route of Drug Administration
1. Sublingual/(buccal)
• Certain drugs are best given beneath the tongue (sublingual) or retained in t
cheek pouch (buccal) and are absorbed from these regions into the local blo
circulation.
• These vascular areas are ideal for lipid-soluble drugs that would
metabolized in the gut or liver, since the blood vessels in the mouth bypass t
liver (do not undergo first pass liver metabolism), and drain directly into t
systemic circulation.
• This route is usually reserved
for nitrates and certain hormones.
 Enteral Route of Drug Administration
2. Oral route: (the most common route.)
oThe passage of drug from the gut into the blood is influenced by biologic and
physicochemical factors and by the dosage form.
oGenerally, the bioavailability of oral drugs follows the order:
solution > suspension > capsule > tablet > coated tablet.
EXTENSIVELY SUBJECTED TO
LIVER METABOLISM
First pass metabolism
 A. Enteral Route of Drug Administration
3. Rectal The administration
Suppositories is usually reserved for situations in which oral administration is
difficult.
This route is more frequently used in small children.
It by-passes the liver
Examples:
Suppositories
Enema
 B. Parenteral Route of Drug Administration
Intravenous injections:
oUsed when a rapid clinical response is necessary, e.g., an acute asthmatic
episode.
oThis route allows one to achieve relatively precise drug concentrations in the
plasma, since bioavailability is 100%.
oMost drugs should be injected over 1-2 minutes
to prevent the occurrence of very high
drug concentrations in the injected vein,
possibly causing adverse effects.
oSome drugs, particularly those with narrow
therapeutic indices or short half-lives, are best
administered as a slow IV infusion or drip
 B. Parenteral Route of Drug Administration
➢Intramuscular injection:
Drugs may be injected into the
• Arm (deltoid),
• Thigh (vastus lateralis) or
• Buttocks (gluteus maximus).
Because of differences in vascularity, the rates of absorption differ,
with arm > thigh > buttocks.
Drug absorption may be slow and erratic.
Lipid solubility and degree of ionization influence absorption.
 B. Parenteral Route of Drug Administration
➢Subcutaneous injection:
Some drugs, notably insulin, are routinely administered SC.
Drug absorption is generally slower SC than IM, WHY?
due to poorer vascularity.
o Absorption can be facilitated by heat, massage or vasodilators.
oIt can be slowed by coadministration of vasoconstrictors,
to prolong the local action of local anaesthetics.
 C. Topical Route of Drug Administration
a. Eye For desired local effects.
b. Intravaginal For infections or contraceptives.
c. Intranasal For alleviation of local symptoms.
Drug absorbed directly from nasal capillaries into circulation..
 C. Topical Route of Drug Administration
D. Skin Systemic absorption does occur and
o varies with the area, site, drug, and state of the skin.
o Dimethyl sulfoxide (DMSO) enhances the percutaneous absorption of many
drugs.
o Drug patches (drug enters systemic circulation by zero order kinetics – a
constant amount of drug enters the circulation per unit time).
 C. Topical Route of Drug Administration
E. Inhalation
oVolatile anesthetics as well as many drugs which affect pulmonary function,
are administered as aerosols.
oThe large alveolar area and blood supply lead to rapid absorption into the
blood.
oDrugs administered via this route are not subject to first-pass liver metabolism.
 Non peroral extravascular routs of administration
o These are other than oral not directly in veins which by-pass GIT (first pass
metabolism) and enter into blood circulation
Examples:-
• Buccal/ sublingual,
• Nasal,
• IM route,
• Topical,
• Rectal,
• S C,
• Vaginal,
• Intraocular
 Why are there Different Routes of Drug Administration?
oSolubility or stability of the drug
Example: The absorption from the different sites.
many drugs are absorbed from stomach and small intestine and not absorbed
rectally.
oToxic when given by certain routes.
oIneffective, destroyed or inactivated in certain organs
Example:
penicillin in stomach
oConvenience of the patient
 Main factors affecting oral absorption:
oPhysiological factors
o Physical-chemical factors (lipophilic, lipophobic, size…)
o Formulation factors
Solution > suspension > capsules > Tablets > Coated tablets
o Excipients
 Excipients as factor affecting absorption
o The more the number of Excipients in the dosage form, the more complex it is & greater the
potential for absorption and Bioavailability problems.
o Commonly used excipients in various dosage forms are:-
a. Vehicle: Rate of absorption –depends on its miscibility with biological fluids.
* Miscible vehicle causes rapid absorption e.g., propylene glycol.
* Immiscible vehicles- Absorption depends on its partitioning from oil phase to aqueous
body fluid.
b. Diluents:
* Hydrophilic diluents- Imparts absorption (Increase)
* Hydrophobic diluents – Retards Absorption
* Also, there is Drug-Diluent interaction forming insoluble complex and retard absorption
Example:
Tetracycline and Dibasic calcium phosphate (DCP)
 Excipients as factor affecting absorption
o Binders and granulating agents:
- imparts hydrophilic property to the granule surface
- gives better dissolution property
Example: Starch, gelatine and PVP
More amount of binder increase the hardness, retard dissolution and absorption rate.
Disintegrants:
* Mostly hydrophilic in nature
* Decrease amount of disintegrant significantly lower absorption and bioavailability
Lubricants:
* Commonly hydrophobic in nature
* inhibits penetration of water into tablet and thus dissolution, disintegration and absorption
Suspending agents/viscosity agent:
* Stabilized the solid drug particles and thus affect drug absorption.
* Macromolecular gum forms un-absorbable complex with drug.
Example: Na CMC
* Viscosity imparters – act as mechanical barrier to diffusion of drug from dosage form
and retard GIT transit of drug.
 Excipients as factor affecting absorption
• Surfactants:
- May enhance or retards drug absorption by interacting with drug or membrane or both.
Example: Griseofulvin, steroids
- It may decrease absorption when it forms the un-absorbable complex with drug above
CMC.
Coating:
Enteric coat
Sugar coat
Non-enteric coat
* The dissolution profile of certain coat change on aging causing low dissolution and can be
prevented with little PVP in the coat.
Buffer:
* May improve dissolution but certain buffer containing potassium cations inhibit drug
absorption of vitamin B2 and sulphanilamide.
Colorants:
* Even low concentration of water-soluble dye can have an inhibitory effect
o Example: Brilliant blue retards dissolution of sulfathiazole.
 Excipients as factor affecting absorption
o Complexing agents:
* Complexing agents are used to modify physicochemical and
biopharmaceutical properties of drug.
Example:
1. Enhanced dissolution through formation of a soluble complex, e.g.,
ergotamine tartrate-caffeine complex & hydroquinone-digoxin complex.
2. Enhanced lipophilicity for better membrane permeability, e.g.,
caffeine-PABA complex
 Physiological Factors Affecting Oral Absorption
A- Membrane physiology
B- Passage of drugs across membranes:-
oActive transport
o Facilitated diffusion
o Passive diffusion
o Endocytosis
o Pore transport
o Ion pair formation
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 Physiological Factors Affecting Oral Absorption
C- Gastrointestinal physiology
o GIT physiology and drug absorption
o Gastric emptying time and motility ( Emptying Absorption)
oEffect of food on drug absorption
oEnterohepatic circulation
oFirst pass effect

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 A. Membrane physiology

Membrane structure (Fluid Mosaic Model):-

o The biologic membrane consists mainly of a lipid bilayer
containing primarily phospholipids and cholesterol, with imbedded
proteins.
oThe membrane contains also small aqueous channels or pores.
 A. Membrane physiology

Phospholipid Bilayers:-
o Phospholipids are amphiphilic in nature.
Cholesterol:-
oCholesterol makes the membrane less permeable to most biological
molecules.
Proteins :-
oProteins are scattered throughout the membrane. They may be
attached to inner surface, embedded in the bilayer, or attached to the
outer surface.
Function of cell proteins
 B. Passage of Drugs Across Membranes

The membrane can be viewed as a semipermeable lipoidal sieve that

allows the passage of: -
olipid-soluble molecules across it by passive lipid diffusion
owater and small hydrophilic molecules through its numerous
aqueous pores.
oother molecules by a number of transporter proteins or carrier
molecules that exist in the membrane.
 ❖ Mechanisms of drug transport across the gastrointestinal
epithelium:
There are two main mechanisms:-
oParacellular: i.e., between the cells.
oTranscellular: i.e., across the cells
o The transcellular pathway is further divided into simple passive
diffusion, carrier-mediated transport (active transport and facilitated
diffusion) and endocytosis.

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 Mechanisms of drug transport across the gastrointestinal epithelium:

oThe rate of transport of drug across the membrane can be described

by Fick's first law of diffusion:-

𝑑𝑀 𝐷. 𝐴 (𝐶ℎ −𝐶𝑙)
Rate of diffusion =
𝑑𝑡 =
𝑋
D: diffusion coefficient
This parameter is related to:
• the size of the drug
• lipid solubility of the drug
• viscosity of the diffusion medium,
As lipid solubility increases or molecular size decreases then D
increases and thus diffusion rate also increases.
 Mechanisms of drug transport across the gastrointestinal
epithelium:
A: surface area As the surface area increases the rate of diffusion also
increase
x: membrane thickness The smaller the membrane thickness the
quicker the diffusion process.
(Ch -Cl): concentration difference:-
Normally Cl << Ch then:- Thus the absorption of many drugs from
the G-I tract can often appear to be first-order. (depend on
concentration)
2. DRUG DISTRIBUTION
 2. DRUG DISTRIBUTION

Distribution
Distribution is the process by which a drug diffuses or is transferred from
intravascular space to extravascular space (body tissues).
o After a drug is absorbed into the bloodstream, it rapidly circulates through
the body; the average circulation time of blood is 1 minute.
o As the blood recirculates, the drug moves from the bloodstream into the
body's tissues.
o Distribution is generally uneven because metabolism and excretion occur
simultaneously with distribution, making the process dynamic and complex.
 2. DRUG DISTRIBUTION
Factors affecting distribution

Extent of distribution: Rate of distribution:

- Lipid solubility - Membrane permeability
- pH- pKa - Blood perfusion
- Plasma protein binding
- Intracellular binding

• For poorly perfused tissues (e.g., muscle, fat), distribution is very slow.
• Water-soluble drugs tend to stay within the blood and the fluid that surrounds cells (interstitial space).
• Fat-soluble drugs can cross cell membranes more quickly than water-soluble drugs and tend to concentrate in
fatty tissues or rapidly enters the brain (e.g., anesthetic thiopental a highly fat-soluble drug(.
 2. DRUG DISTRIBUTION
Factors affecting distribution

• Other drugs concentrate mainly in only one small part of the body (for
example, iodine concentrates mainly in the thyroid gland), because the tissues
there have a special attraction for and ability to retain (affinity) the drug.
• Some drugs leave the bloodstream very slowly, because they bind tightly to
proteins circulating in the blood.
• Others quickly leave the bloodstream and enter other tissues, because they are
less tightly bound to blood proteins.
 2. DRUG DISTRIBUTION
o After Distribution equilibrium (when entry and exit rates are the same), drug
concentrations in tissues and in extracellular fluids are reflected by the plasma
concentration.
o The body is usually divided into two spaces, a central and a tissue
(peripheral) compartment .

1. Central Compartment
This compartment can be thought of as
the blood in vessels and
tissues which are highly perfused by blood
(e.g., heart, liver, brain and kidney).
 2. DRUG DISTRIBUTION

2. Peripheral Compartment(s)
• Which are less well-perfused include(s)
o those organs (e.g., adipose and skeletal muscle), and,
o with which drug therefore equilibrates more slowly.
3. Special Compartments
o These include cerebrospinal fluid (CSF) and central nervous system (CNS).
o The blood-brain barrier limits the success of antibiotics, anticancer drugs and
other agents used to treat CNS diseases
 2. DRUG DISTRIBUTION

Other special compartments to which drugs also have relatively poor access to
are pericardial fluid, bronchial secretions and fluid in the middle ear, thus
making the treatment of infections in these regions difficult.
 2. DRUG DISTRIBUTION
❖Redistribution from one compartment to another often alters the duration of
effect at the target tissue.
e.g., thiopental is highly lipid soluble
o It rapidly enters the brain after a single IV injection, and has a marked and
rapid anesthetic effect;
o the effect ends within a few minutes as the drug is redistributed to more
slowly perfused fatty tissues.
➢ Thiopental is then slowly released from fat storage, maintaining
subanesthetic plasma levels; these levels may become significant if doses of
thiopental are repeated, causing large amounts to be stored in fat.
➢ Thus, storage in fat initially shortens the drug's effect but then prolongs it.
 2. DRUG DISTRIBUTION
Volume of Distribution (Vd)
• Vd is an indicative of the extent of distribution of a drug.
• Vd does not represent a real volume, but rather indicates a theoretical volume of fluid into
which the total drug administered would have to be diluted to produce the concentration in
plasma.

• The volume of distribution could be defined as:

Reflection of the amount left in the blood stream after all the drug has been absorbed
▪ if drug is ‘held’ in the blood stream it will have a small volume of distribution
▪ if very little drug remains in blood steam has a large volume of distribution
 2. DRUG DISTRIBUTION
• Volume of Distribution (Vd)
𝐷𝑂𝑆𝐸(𝐷)
𝑣𝑑 =
𝑃𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐. (𝐶𝑝).

❖For example, if 1000 mg of a drug is given and the

subsequent plasma concentration is 10 mg/L, that 1000 mg
seems to be distributed in 100 L.
 2. DRUG DISTRIBUTION
Factors influencing Vd:

1. Protein Binding
• Many drugs bind to plasma proteins especially albumin.
• Only that fraction of the plasma drug concentration which is freely circulating
(i.e., unbound) can penetrate cell membranes (active).
• Protein binding thus decreases the net transfer of drug across membranes and Vd will be
small.
• Drug binding to plasma proteins is generally weak and rapidly reversible,
• So that protein-bound drug can be considered to be in a temporary storage compartment
 2. DRUG DISTRIBUTION
2. Extravascular binding
• Binding to tissue proteins e.g. receptors or storage in fat or other tissues will
result in a large Vd.
• For example, digoxin, a hydrophobic drug which distributes into fat and
muscle, has a Vd of 640 liters (in a 70 kg man), approximately nine times the
total volume of the man!
• In general, acidic drugs bind to plasma proteins and have small Vds, while
basic drugs tend to bind more extensively to extravascular sites and have
larger Vds.
 2. DRUG DISTRIBUTION
3. Personal differences
➢ Disease
o Vd may be influenced by disease states.
o For example, patients with chronic liver disease have lower serum albumin
concentrations.
o Plasma protein binding will be reduced, leading to lower plasma drug concentrations and
higher Vds
 2. DRUG DISTRIBUTION
3. Personal differences
➢ Obesity
o Obese people may store large amounts of fat-soluble drugs in adipose tissues (large Vd),
o whereas very thin people may store relatively little.

➢ Age
o Older people, even when thin, may store large amounts of fat-soluble drugs because the
proportion of body fat increases with age.
 2. DRUG DISTRIBUTION

Distribution of THC (tetrahydrocannabinol) after a single

administration in plasma and body tissues. Lipophilic Drug
 3. DrugMetabolism
Biotransformation

Metabolism also known as Biotransformation

Bio Transformation

Alteration or
Within Body
Change
 3. Drug Metabolism
Biotransformation

DRUG BIOTRANSFORMATION

What is meant by xenobiotics?

oThe body is exposed to a wide variety of foreign compounds, called

xenobiotics.

oExposure to some such compounds is unintentional (e.g., environmental or

food substances), while others are used as drugs.

oThe following discussion of drug biotransformation is applicable to all

xenobiotics, and to some endogenous compounds (e.g., steroids) as well.
 3. Drug Metabolism
Biotransformation

The kidneys are capable of eliminating drugs which are:

- low in molecular weight or
- polar and fully ionized at physiologic pH.

➢Most drugs do not fit these criteria, but rather are fairly large, unionized or
partially ionized, lipophilic molecules
 3. Drug Metabolism
Biotransformation
Definition
Biotransformation is the chemical or enzymatic alteration of drug in the body
that converts:-
oActive drug into inactive drug
o Non-polar drugs to polar drugs
o lipid soluble drug into water soluble (lipid insoluble)
oLiver is the main site of metabolism for most drugs.
oCytochrome P-450 enzymes group involve in the metabolism of drugs
 3. Drug Metabolism
Biotransformation

The kidneys are capable of eliminating drugs which are:

- low in molecular weight or
- polar and fully ionized at physiologic pH.
Most drugs do not fit these criteria, but rather are fairly large, unionized or
partially ionized, lipophilic molecules

The general goal of drug metabolism is to

transform such compounds into more polar
(i.e., more readily excretable)
water soluble products.
 3. Drug Metabolism
Biotransformation

For example, without biotransformation to more water-soluble products,

thiopental, a short-acting, lipophilic anesthetic, would have a half-life of more
than 100 years!
 3. Drug Metabolism
Biotransformation

1. Most products of drug metabolism are less active than the parent compound.
2. In some cases, however, metabolites may be responsible for toxic, mutagenic,
teratogenic or carcinogenic effects.
oFor example, overdoses of acetaminophen owe their hepatotoxicity to a minor
metabolite which reacts with liver proteins.
 3. Drug Metabolism
Biotransformation

3. In some cases, some drug metabolites are also pharmacologically active

sometimes even more so than the parent compound.
oAn inactive or weakly active substance that has an active metabolite is called a
prodrug.
o The best example of a prodrug is cyclophosphamide, an inert compound
which is metabolized by the liver into a highly active anticancer drug.
 3. Drug Metabolism
Biotransformation

3. Rate of drug metabolism

• Drug metabolism rates vary among patients.
• Some patients metabolize a drug so rapidly that therapeutically effective blood
and tissue concentrations are not reached;
• in others, metabolism may be so slow that usual doses have toxic effects.
 3. Drug Metabolism
Biotransformation
Individual drug metabolism rates are influenced by:
● genetic factors
● coexisting disorders (particularly chronic liver disorders and advanced
heart failure)
● drug interactions (especially those involving induction or inhibition of
metabolism)
 3. Drug Metabolism
Biotransformation

• A. Sites of drug metabolism

• 1. At the organ level
• The liver is the primary organ of drug metabolism.
• The gastrointestinal tract is the most important extrahepatic site.
• Some orally administered drugs are conjugated extensively in the intestinal
epithelium, resulting in decreased bioavailability.
• The lung, kidney, skin and placenta can also carry out drug metabolizing
reactions.
 3. Drug Metabolism
Biotransformation

2. At the cellular level

oMost enzymes involved in drug metabolism are located within the
lipophilic membranes of the smooth endoplasmic reticulum (SER).
oMost of the enzymes carry out oxidation reactions.

Remember: The smooth endoplasmic reticulum, rich in a

wide variety of enzymes, is most common in cells which are
involved in the synthesis of lipids, triglycerides, lipoprotein
complexes, and steroids .
 3. Drug Metabolism
Biotransformation

B. Mechanism of drug metabolism

For many drugs, metabolism occurs in 2 phases.
Phase I reactions
refer to those which convert a drug to a more polar compound by
introducing or unmasking polar functional groups such as - OH,
-NH2, or –SH by e.g. oxidation, hydroxylation, reduction or
hydrolysis (of esters & amides).
 3. Drug Metabolism
Biotransformation

PHASE 1 reactions

Hydroxylation -CH2CH3 -CH2CH2OH

Oxidation -CH2OH -CHO -COOH

N-de-alkylation -N(CH3)2 - NHCH3 + CH3OH

Oxidative deamination -CH2CHCH3 -CHCOCH3 + NH3

|

NH2
 3. Metabolism
Biotransformation

Phase II reactions
• Conjugations with glucuronic acid
➢ - OH, -SH, -COOH, -CONH with glucuronic acid to give
glucuronides
• Conjugations with sulfate
➢ - OH with sulfate to give sulfate
 3. Drug Metabolism
Biotransformation

OH O-SO3

Phase I Phase II

Metabolites formed in phase 2 reactions are more polar and more readily
excreted by the kidneys (in urine) and the liver (in bile) than those formed
in phase 1 reactions.

However, some drugs undergo only phase I or phase II reactions.

 3. Drug Metabolism
Biotransformation

In some cases, a drug may undergo a series of consecutive reactions

resulting in the formation of dozens of metabolites.

Most phase I biotransformation reactions are oxidative in nature and

require:
reducing agent (NADPH),
molecular oxygen, and
microsomal enzymes
 3. Drug Metabolism
Biotransformation

o the oxidizing enzyme is called cytochrome P450, a hemoprotein so named

because its carbon monoxide derivative absorbs light at 450 nm.

o Cytochrome P450 is a family of enzymes which differ primarily with

regard to their substrate specificities.

o CYP-450 enzymes can be induced or inhibited by many drugs and

substances.
 3. Drug Metabolism
Biotransformation

C. Enzyme Induction

o An interesting and important feature of the cytochrome P450 mixed

function oxidase system is the ability of some xenobiotics to induce the
synthesis of new enzyme.

o Microsomal enzyme induction is a complex process associated with an

increase in liver weight, proliferation of the SER, and synthesis of P450
enzymes.
 3. Drug Metabolism
Biotransformation

o Enzyme induction will shorten action of drugs or

increase effects of prodrugs

For example:

phenobarbital induces the P450IIB subfamily, while polycyclic aromatic

hydrocarbons (found in cigarette smoke) induces the P450IA subfamily

 3. Drug Metabolism
Biotransformation

Example on possible effects of enzyme inducers:

o For example, consider patients who routinely ingest barbiturates or
tranquilizers (P450 inducers) who must, for medical reasons, be treated
with warfarin or dicumarol (oral anticoagulants).
o Because of a faster rate of drug metabolism, the dose of warfarin will
need to be high.
o If the patient should for some reason discontinue the barbiturates, the
blood level of warfarin will rise, perhaps leading to a bleeding disorder.
 3. Drug Metabolism
Biotransformation

D. Enzyme Inhibition
o Relatively few xenobiotics are known to inhibit microsomal enzymes.
Example for enzyme inhibitors:
●cimetidine, a widely used anti-ulcer drug, is an important, potent inhibitor
of microsomal drug metabolism
●thus retards the metabolism of many other drugs, including warfarin and
similar anticoagulants, theophylline and caffeine, phenobarbital and
diazepam.
Enzyme inhibition will prolong action of drugs or
decrease effects of prodrugs
 Effect of aging on metabolism

Effect of aging on metabolism

o With aging, the liver's capacity for metabolism through the CYP-450
enzyme system is reduced by ≥ 30% because liver volume and hepatic
blood flow are decreased.
o Thus, drugs that are metabolized through this system reach higher levels
and have prolonged half-lives in the elderly
 Effect of aging on Drug Metabolism
Biotransformation

Plasma concentration of diazepam in a younger man (A) and an older man (B).
What about neonates?
Because neonates have partially developed liver microsomal enzyme
systems, they also have difficulty metabolizing many drugs.
 Factors Affecting Metabolism

1. Enzyme induction:-
Some drugs like phenobarbitone and Rifampicin can increase drug metabolism
by increasing cytochrome p-45 enzyme.
2. Enzyme inhibition:-
Some drugs like omeprazole, cimetidine decrease drug metabolism by
inhibiting cytochrome p-45 that metabolize the drug
3. Age:-
Metabolism occurs in adult more than children and elder people may be due to
decrease in enzyme production for liver in-convent
 Factors Affecting Metabolism

4. Gender (sex):-
Metabolism fast occurring in males in comparison to females
5. Species:-
Some drugs like atropine easily metabolized in animals (rabbits) but not in
Humans, because rabbits posse enzyme Atropines
6. Disease state:-
oSome disease like liver failure, liver inflammation (Jaundice) affect drug
metabolism.
oCHF (congestive heart failure) decrease blood flow to the liver and decrease
metabolism
 4. Excretions (Elimination)
Excretion means, removal of drug or metabolites from body by renal
(kidney) or Non-renal routes

Types and Routes of Excretion:-

1. Renal excretion:- when drug is eliminated by kidneys
- about 80% drug are eliminated by kidneys.
- Hydrophilic drugs excreted through URIN.
 4. Excretions (Elimination)

2. Non-renal Excretion:-
Drug excreted with other routes and not through kidneys
i. Biliary (Faeces, stool), some drugs excreted in faeces.
ii. Pulmonary Excretion, by Lungs
iii. Salivary excretion, through saliva
iv. Skin excretion, by sweat
v. Mammary excretion, by mother’s Milk.
the latter a possible source of unwanted exposure in nursing infants
 4. Excretions (Elimination)

Mechanisms of Renal Function

Three of the biggest jobs that the kidneys have are:
(1) to cleanse the blood
(2) to regulate and maintain an appropriate fluid and chemical balance in
the body
(3) to produce the urine
 4. Excretions (Elimination)

➢Portion of the plasma water and its solutes are transferring

continuously from the blood to the renal tubule.

The renal tubule, modifies the tubular fluid and returns about 98 to
99% of it to the body as a fluid whose composition and volume is
ideal for sustaining normal body functions.

Only that which is not useful, potentially harmful or present in

excess of the body’s needs escapes into the urine.
 4. Excretions (Elimination)

➢Drug excretion

There are 4 processes

The drug may follow one or more of the following processes:

A. Renal Glomerular Filtration

➢Glomeruli permit the passage of most drug molecules, but, restrict the
passage of protein-bound drugs.
 4. Excretions (Elimination)

B. Renal Tubular Secretion

oThe kidney can actively transport some drugs (e.g., dicloxacillin) against a
concentration gradient, even if the drugs are protein-bound. (Actually, only
free drug is transported.
oA drug called probenecid competitively inhibits the tubular secretion of the
penicillin and may be used clinically to prolong the duration of effect of the
penicillin.
 4. Excretions (Elimination)

C. Renal Tubular Reabsorption

oMany drugs are passively reabsorbed in the renal tubules.

oReabsorption is influenced by the same physicochemical factors that influence

gastrointestinal absorption:

➢Nonionized, lipid-soluble drugs are extensively reabsorbed into plasma, while

ionized and polar molecules will remain in the renal filtrate and be excreted
via urine.
 4. Excretions (Elimination)

➢Thus, as in the gut, urine pH plays an important role.

➢ Urine pH may vary widely from 4.5 to 8.0, may be influenced by diet,
exercise, or disease, and tends to be lower during the day than at night.
➢It is sometimes clinically useful, particularly in drug overdose cases, to alter
the pH of the urine (of the patient).
➢For drugs which are weak acids, urine alkalinization favors the ionized form
and promotes excretion.
➢Alternatively, acidification promotes the renal clearance of weak bases,
WHY?
 4. Excretions (Elimination)

D. Biliary Excretion

oMany drugs and metabolites are passed into the small intestine via bile and
may undergo enterohepatic cycling.

oRecent studies have attempted to interrupt enterohepatic cycling of drugs,

pesticides and heavy metals through the oral administration of non-
absorbable, nonspecific adsorbents such as charcoal or cholestyramine
 Factors Affecting Excretions (Elimination)

1. Physiological Properties of Drug:-

Are properties of drug which affect excretion
i. Molecular weight
Low molecular weight produce high excretion
ii. Lipid solubility (mean at excretion time drug should be
hydrophilic)
low lipid solubility increase drug excretion
 Factors Affecting Excretions (Elimination)

iii. Ionization,
Ionized drug = Hydrophilic drug = Increase Excretion
2. Blood flow to kidney (blood perfusion):-
High perfusion increase Excretion
3. pH:-
Acidic drugs are easily excreted because Urine pH is acidic
 Factors Affecting Excretions (Elimination)

4. Age:-
Best excretion occurs in Adults in comparison to children and elderly
5. Disease state:-
In some diseases like Diabetes, Kidney failure and Hypertension
Excretion is Affected …..HOW?