Pharmacokinetics
(Absorption, Distribution,
Metabolism & Excretion)
I. ABSORPTION
• Absorption is the transfer of a Drug from the site of exposure into the
systemic circulation.
• During this process, drugs cross body membranes and enter the
bloodstream.
• No absorption= No effect
Main absorption routes/barriers are
1.Oral-gastro intestinal tract (GIT)
2.Parenteral(IM, Sc)
3. Inhalation-lung
4.Dermal-skin
Drugs must cross one of these barriers to exert their action in the
body. However during this process they usually pass through various
cell membranes.
Structure of a cell membrane
Basic mechanisms of drug transmembrane
transport
A drug may pass through a membrane by;
1. Passive Transfer
i. Simple diffusion
ii) Filtration
2. Specialized transport
i) Facilitated diffusion
ii) Active transport
iii) Endocytosis (phagocytosis and pinocytosis)
Factors affecting absorption
1.Factors related with chemical.
a. Physio chemical properties
b. Concentration at absorption site
c. Physical form
d. Acidity and basicity of drug
2.Factors related withsite of exposure
a. Blood flow
b. Surface area and permeability
c. contact time
Factors related with chemical(drug)
a. Physiochemical properties
i. Mol. weight: Small molecules are readily absorbed.
ii. Lipid/water solubility: Lipid solubility increases the absorption and
vice versa .
iii. Ionization degree of a chemical :The ionized form usually has low
lipid solubility and thus does not cross readily through the lipid domain
of a membrane.
b. Concentration at exposure site: Generally high concentration
results with higher absorption.
c. Physical form: Liquids are absorbed better than solids.
d) Acidity and basicity and pH:
Acidic drugs: well Absorbed from the stomach e.g. salicylates
Basic drugs: Well absorbed in the alkaline environment i.e. small
intestine when administered orally e.g. pethidine and ephedrine
2. Factors related with site of exposure
a. Blood flow rate at site of exposure:High perfusion results high rate
absorption rate
b. Surface area and permeability: intestines has larger surface area (microvilli
and villi ) then stomach so most of drugs are absorbed from intestine.
c.Contact time at site absorption: if the drug moves through GIT tract very quicly,
it is not well absorbed and vice versa.
3. Pharmacogenetic factors: Individual variations occur due to the genetically
mediated reason in drug absorption and response
distribution
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Distribution
Drug distribution is the process of delivering a drug from the bloodstream to
the tissues of the body – especially the tissue(s) where its actions are
needed.
The process of transferring a drug from the bloodstream to tissues is
referred to as distribution.
Factors affecting
Distribution
Blood flow
Capillary permeability
Lipid Solubility
Binding of drugs to plasma proteins and tissue protiens
Biotransformation(metabolism)
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• Biotransformation(metabolism) means
chemical alteration of the drug in the body.
• It is needed to render lipid-soluble drugs to
water soluble so that they are not reabsorbed
in the renal tubules and are excreted.
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Sites of biotransformation
• Liver
• Primary site! Rich in enzymes
• Acts on endogenous and exogenous compounds
• Extrahepatic metabolism sites
• Intestinal wall
• Lungs, kidney, placenta, brain, skin, adrenal glands
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Biotransformation of drug may lead to the following
• Inactivation
Salicylic Acid (active) Salicyluric acid(inactive)
• Active metabolites
Amitryptiline (active) Nortryptiline(active)
• Prodrug
Enalpril(in active) Enalaprilat(active)
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Phases of metabolic reactions
Metabolic reactions may be classifed into
phase I (non synthetic) and Function of phase I reactions is to attach a functional
group to the drug molecule.
• After phase I reaction, drug may be water soluble or lipid soluble
phase II (synthetic) reactions.
• phase II reactions serve to attach a conjugate to the drug molecule.
• after phase II reaction, all drugs become water soluble.
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Phase I reactions
oxidation
Reduction
Hydrolysis
phase II reactions
Glucuronidation
Acetylation
Methylation
sulfation and glycine conjugation.
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Phase 1 reactions
• Phase 1 reactions involve the biotransformation of a
drug by one or more of the following reactions to a
more water-soluble metabolite, which is more likely to
be excreted by the kidney or go on to Phase 2.
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A. Oxidation reaction
• Oxidation is the most important and commonest type of
metabolic reaction, which involves the addition of
oxygen to the drug molecule.
• In the liver, oxidation reactions are catalyzed by a
group of enzymes known as the microsomal mixed
function oxidase system or the cytochrome P450
enzyme family.
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B. Reduction
• Reduction reactions involve the removal of oxygen or the
addition of hydrogen to the drug molecule.
• Halothane and warfarin are examples.
• Enzymes capable of catalyzing reduction reactions are found in
many body tissues, including the liver and in the intestinal
bacteria.
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C. Hydrolysis
• Hydrolysis involves the splitting of a drug molecule by
the addition of water.
• aspirin, carbamazepine,pethidine and oxytocin are
examples.
• Enzymes capable of catalysing hydrolysis are found in
many body tissues but particularly in the small intestine
• Esterases and Amidase.
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Phase 2 reaction
• Phase 2 metabolism involve coupling an endogenous substrate to a drug
or to phase one metabolite
• make drugs or Phase 1 metabolites into more hydrophilic, less toxic
substances
• This too encourages renal excretion.
Acetyl group via acetylation
• e.g. sulfonamides, isoniazid, and hydralazine.
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• Glucuronyl group via glucuronidation
Examples are—chloramphenicol, aspirin, paracetamol, diazepam,
Methyl group via methylation
e.g. adrenaline, histamine, nicotinic acid, methyldopa and captopril.
Sulfa group via sulphation
e.g. chloramphenicol, methyldopa, adrenal and sex steroids.
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Drug metabolizing enzymes
Metabolism may occur with the help of
• microsomal (present in smooth endoplasmic reticulum)
• non-microsomal enzymes(present in the cytoplasm and mitochondria)
• Microsomal enzymes (monooxygenases, cytochrome P450 and glucoronyl
transferase) may be induced or inhibited by other drugs whereas non-
microsomal enzymes are not subjected to these interactions.
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Summary of the P450 system
The P450 system is important for the metabolism of
many endogenous compounds (steroids, lipids, etc.)
and for the biotransformation of exogenous substances
(xenobiotic).
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Cnt…
• Cytochrome P450, designated as CYP, is composed of
many families of heme-containing isozymes that are
located in most cells but are primarily found in the liver
and GI tract.
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Cnt…………..
• Six isozymes are responsible for the vast majority
of P450-catalyzed reactions:
• CYP3A4
• CYP2D6
• CYP2C9/10
• CYP2C19
• CYP2E1
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•
Cnt………..
The percentages of currently available drugs that are substrates for
these isozymes are 60, 25, 15, 15, 2, and 2 percent, respectively.
Note: An individual drug may be a substrate for more than one
isozyme.
Considerable amounts of CYP3A4 are found in intestinal mucosa,
accounting for first-pass metabolism of drugs such as
chlorpromazine and clonazepam.
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Factors affecting metabolism of drugs
There are many factors that can affect the metabolism of
drugs
• Enzyme induction
• Enzyme inhibition
• Age
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Enzyme induction
• Some drugs are capable of increase the synthesis of
microsomal enzyme protein, especially cytochrome P-450.
• This is known as enzyme induction and occurs when a drug is
administered over a period of time.
• Its significance is that other drugs metabolized by the same
enzymes are metabolized faster and therefore circulate in a
lower concentration than expected for a given dose.
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• Examples of drugs that are well known to cause enzyme
induction are
• carbamazepine( antiepileptics)
• phenytoin (antiepileptics) and
• alcohol
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Enzyme inhibition
• One drug can competitively inhibit the metabolism of another if it
utilizes the same enzyme or cofactors.
• The effects of inhibition can appear as soon as the inhibiting
drug reaches a high enough concentration to compete with
another drug for the same enzymes.
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• Cimetidine, a drug used to treat stomach ulcers, can inhibit the
metabolism of several potentially toxic drugs such as phenytoin
(antiepileptic), warfarin (anticoagulant) and theophylline
(bronchodilator).
• Erythromycin, an antibiotic, similarly increases the activity of
theophylline, warfarin and digoxin (used in cardiac failure)
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Age
• Age can have an effect on the way the body metabolizes drugs.
• Both liver function and the number of hepatic enzymes are
reduced at birth (especially in preterm infants).
• However, these develop rapidly during the first 4 weeks of life.
• In the elderly the metabolism of drugs declines because of a
reduction in hepatic enzymes.
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Thank You
