PHARMACOKINETICS
-I
BIOAVAILABILITY &
DISTRIBUTION
DR. USHA V.
NAYAK
PROFESSOR &
HEAD
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Overview of the Session
★ Definition of Pharmacokinetics
★ Transport Processes of Drugs
★ Drug Absorption
★ Bioavailability
★ Absorption versus Bioavailability
★ Factors affecting Absorption & Bioavailability
★ Absolute versus Relative Bioavailability
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Overview of the Session
★ Drug Distribution
★ Factors affecting Distribution
★ Plasma Protein Binding
★ Lipid versus Water Solubility
★ Volume of Distribution
★ Tissue Binding of Drugs
★ Redistribution
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Pharmacokinetics
★ It is the study of the absorption,
distribution, storage
,biotransformation and elimination
of a drug
★ It is the movement of the drug in
the body
★ It is what the ‘body does to the
drug’
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Transport Processes : Diffusion
It is the net movement of a
substance from a region of
higher concentration to a
region of lower
concentration
It is driven by a
concentration gradient
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Transport Processes : Facilitated Diffusion
It is the process of biological
transport in which specific
structural components of
biological membranes interact
with particular solutes or
classes of solutes, markedly
increasing the rates at which
they can cross the membrane
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Transport Processes : Active Transport
Active Transport is defined
as a process that involves
the movement of molecules
from a region of lower
concentration to a region of
higher concentration against
a gradient with the use of
energy
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Drug Absorption
Importance of Drug Absorption
★ To predict the onset of action
★ To ascertain the biological lag ( Time between administration
and onset of response)
★ To determine frequency of administration
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Drug Absorption
On oral administration, absorption occurs mainly in the upper
gastrointestinal tract
Drugs administered orally can be inactive systemically , for the
following reasons :
★ Enzymatic degradation of polypeptides by gastric acid
★ Poor gastro-intestinal absorption
★ Hepatic First pass metabolism
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Bioavailability
★ It is the amount or percentage of active drug that is
absorbed from a given dosage form and reaches the
systemic circulation following non-vascular
administration
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Bioavailability
★ Thus bioavailability for the same drug is different for every
route of administration
★ It also varies for different dosage forms/formulations of the
same drug when administered by the same route
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Drug Absorption versus Bioavailability
Absorption is the amount of drug that leaves the site
of administration
Bioavailability is the amount of drug that reaches the
systemic circulation /site of action
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Plasma Concentration ( mg/ml)
Calculation of Bioavailability
Dose (mg)
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Calculation of Bioavailability
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Absolute versus Relative Bioavailability
Absolute bioavailability is the amount of drug from a formulation
that reaches the systemic circulation via a given route ,relative to an
identical intravenous dose
Relative bioavailability measures the bioavailability of a
formulation of a certain drug formulation when compared with
another established standard formulation of the same drug in the
same dose and by the same route
Factors affecting Absorption & Bioavailability 16
Dosage Form Factors
Drug Factors Recipient
Factors
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Drug factors affecting Absorption /Bioavailability
Physicochemical Properties of Lipid versus Water Solubility
the Drug ★ Lipid soluble (Lipophilic)
★ Physical State of the drug drugs tend to cross cell
Liquid form is absorbed membranes to a greater
faster than solid form extent than water soluble
e.g. Antacids drugs (Hydrophilic agents)
★ Colloid versus Crystalloid
Colloids are absorbed slower
and to a lesser extent than
crystalloids
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Dosage Form Factors affecting Absorption
/Bioavailability
Particle Size
★ A decrease in particle size , increases the absorption of drug from
the gastrointestinal tract
e.g. Microfine Aspirin
★ When a drug taken orally for an action intended mainly for the
gastrointestinal tract, increasing the particle size will restrict
absorption and confine the agent mainly to the site of action
e.g. Antihelminthic agents
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Dosage Form Factors affecting Absorption /Bioavailability
Disintegration time and Dissolution Time
★ Disintegration Time is the time required for a dosage form to break
up into its constituent particles
★ Tablets with a shorter Disintegration Time will have a more rapid
onset of action
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Dosage Form Factors affecting Absorption /Bioavailability
Disintegration time and Dissolution Time
★ Dissolution Time is the time required for the drug particles to go
into solution
★ Dissolution Time is an indicator of Bioequivalence of an oral solid
dosage form
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Dosage Form Factors affecting Absorption
/Bioavailability
Formulation
★ It is the complete composition of a drug product, including its active
ingredient/s,excipients (diluents ), stabilising , colouring and any
other agents that go to make up the dosage form
Biopharmaceutics
★ It is the study of the influence of formulation on the biological
actions of a drug
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Dosage Form Factors affecting Absorption
/Bioavailability
Chemical Equivalence
Two drug products are said to be chemically equivalent when they
contain identical quantities of the same active ingredient/s , but not
necessarily of the other ingredients of the dosage form
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Dosage Form Factors affecting Absorption
/Bioavailability
Biological Equivalence
Two drug products are said to be biologically equivalent when they yield
identical plasma concentrations of the active ingredient/s in vivo
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Dosage Form Factors affecting Absorption
/Bioavailability
Therapeutic Equivalence
Two drug products are said to be therapeutically equivalent when they
produce identical pharmacological actions in vivo
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Dosage Form Factors affecting Absorption
/Bioavailability
Chemical vs Biological vs Therapeutic Equivalence
★ Ideally , Chemical equivalence should result in Biological
Equivalence which ,in turn should lead to Therapeutic Equivalence
★ Since the pharmacological actions are attributable only to the active
ingredient/s and not to any other constituents
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Dosage Form Factors affecting Absorption
/Bioavailability
Chemical vs Biological vs Therapeutic Equivalence
★ However , different drug products may contain non-identical
ingredients other than the active drug/s
★ This may lead to two Chemically Equivalent Drug Products showing
Biological and Therapeutic Inequivalence
★ Therapeutic Significance : Patient should not switch between drug
brands , unless unavoidable
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Host / Physiological Factors affecting Absorption
/Bioavailability
★ pH and Ionisation
★ Vascularity and area of absorptive surface
★ Presence of food/other agents
★ Enterohepatic recirculation
★ First Pass Metabolism
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Host / Physiological Factors affecting Absorption
/Bioavailability
pH and Ionisation
❖ Most drugs are either weakly acidic or weakly basic in nature
❖ They remain unionised and hence more lipophilic in the same
environment
❖ Weakly acidic drug remains unionised in the acidic pH of the
stomach
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Host / Physiological Factors affecting Absorption
/Bioavailability
pH and Ionisation
❖ Weakly alkaline drug remains unionised in the alkaline pH of the
intestine
❖ Unionised drugs are more lipophilic , hence better absorbed in that
environment
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Host / Physiological Factors affecting Absorption
/Bioavailability
Vascularity and area of absorptive surface
★ The more vascular the absorptive surface , the more is the extent of
absorption from that site
★ Following subcutaneous injection in the thigh, Insulin is absorbed
more on exercise
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Host / Physiological Factors affecting Absorption
/Bioavailability
Presence of food/other agents
★ Presence of food can interfere with absorption of an orally
administered drug
★ Drugs that can cause gastric irritation should be administered after
food e.g. aspirin
★ Increased fat content in the diet can enhance absorption of
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Host / Physiological Factors affecting Absorption
/Bioavailability
Presence of other agents
★ Anticholinergic drugs can delay gastric emptying and interfere with
intestinal absorption of drugs
★ Dairy products can interfere with absorption of Tetracyclines
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Host / Physiological Factors affecting Absorption
/Bioavailability
Enterohepatic recirculation
The process whereby a drug or its metabolite in the liver is secreted into the
bile, stored in the gallbladder, and subsequently released into the small
intestine, where the drug can be reabsorbed back into circulation and
subsequently returned to the liver
Host / Physiological Factors affecting 34
Absorption /Bioavailability
First Pass Metabolism
It is the metabolism of a drug that happens during its passage
from its site of absorption into the systemic circulation
Since enzymes bring about metabolism, and synthesis of
enzymes is dependent on genes , there is inter-individual
variation in first pass metabolism
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Factors affecting Drug Distribution
★ Plasma Protein Binding
★ Lipid Versus Water Solubility
★ Volume of Distribution
★ Tissue Binding of Drugs
★ Redistribution
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Protein Binding of Drugs
★ Certain drugs bind to proteins
in the plasma
★ For a protein bound drug, the
fraction of the drug that binds
to plasma protein remains
constant
★ Protein binding of a drug
follows a dynamic
equilibrium
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Plasma Protein Binding of Drugs
★ If a drug is 90% bound to plasma proteins, the remaining free
form reaches the site of action, brings about the desired effect,
after which this free fraction is metabolised and excreted
★ In order to maintain the equilibrium, 10% of the remaining bound
drug dissociates from protein binding
★ This maintains the Bound : Free ratio in the body
Significance of Plasma Protein Binding of Drugs
★ The Bound form of the drug does not leave the circulation, hence
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is the inactive or reservoir form of the drug
★ The Free form of the drug is the active form of the drug
★ A highly protein bound drug has a long duration of action
★ In conditions of hypoproteinemia , the free form will increase in
the plasma
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Significance of Plasma Protein Binding of Drugs
★ When two highly protein bound
drugs are administered together
, one can displace another from
protein binding
★ This can lead to an increase in
its free concentration
★ This can lead to toxic effects of
the displaced drug
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Lipid versus Water Solubility of the Drug
★ A non-polar, uncharged , non-ionised drug is more lipid soluble
and crosses most cell membranes to a greater extent
★ Thus a lipid soluble drug shows wider distribution in the body
★ Highly lipid-soluble drugs cross the blood brain barrier as well the
placental barrier
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Volume of Distribution (Vd)
★ The volume of distribution (VD, also known as apparent volume of
distribution, literally, volume of dilution[1]) is the theoretical volume
that would be necessary to contain the total amount of an administered
drug at the same concentration that it is observed in the blood plasma
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Volume of Distribution (Vd)
★ In other words, It is the ratio of amount of drug in a body (dose) to
concentration of the drug that is measured in blood, plasma, and
un-bound in interstitial fluid
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Volume of Distribution (Vd)
★ It represents the degree to which a drug is distributed in body
tissue rather than the plasma. VD is directly proportional with the
amount of drug distributed into tissue
★ A higher VD indicates a greater amount of tissue distribution
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Volume of Distribution (Vd)
★ A VD greater than the total volume of body water is possible, and
would indicate that the drug is highly distributed into tissue
★ In other words, the volume of distribution is smaller for the drug
mainly limited to the plasma than that of a drug that is widely
distributed in tissues
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Volume of Distribution (Vd)
Drug properties that limit Volume of Distribution
★ Low lipid solubility (Polar drugs),
★ High rates of ionization
★ Extensive plasma protein binding
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Calculation of Volume of Distribution (Vd)
Vd (L) = A(t) (mg) / C(t) (mg/L)
★ A(t) represents the amount of drug in the body at time = t
★ C(t) represents plasma concentration of the drug at time = t
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Tissue Distribution of Drugs
★ Tissue binding is a major determinant of drug distribution
★ It affects both volume of distribution (as a measure of gross
overall distribution) and site-specific localization
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Tissue Distribution/ Binding of Drugs
Tissue Drug
Adipose Tissue Thiopentone Sodium , DDT
Liver Chloroquine
Cardiac muscle Emetine
Retina Chloroquine
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Significance of Tissue Binding
➢ Chloroquine binds to hepatic tissue sites
➢ Hence when used for the treatment of malaria , a loading dose has
to be administered , in order to saturate these hepatic binding sites
➢ Chloroquine also binds to retinal sites and can produce ocular
toxicity when used long term
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Redistribution
★ The body tissues/organs are of two types
★ Those which do not constitute a large fraction of the body weight
, but are highly vascular e.g brain, liver, kidney, heart
★ The other tissues that are bulky and less vascular e.g. skeletal
muscle,adipose tissue
> <
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Redistribution
★ Highly lipid-soluble drugs given by intravenous or inhalation
methods are initially distributed to organs with high blood
flow. Later, less vascular but more bulky tissues (such as
muscle and fat) take up the drug
★ Plasma concentration falls and the drug is withdrawn from
these sites
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Redistribution
★ This leads to termination of drug action
★ e.g. Thiopentone Sodium , a General Anaesthetic , but due
to a very short half life , used only for induction of
anaesthesia
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Thank you
