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OUTLINE
I. Introduction
II. Site/Organ of drug metabolism
III.Aims and objects of drug metabolism
IV.Process of drug metabolism
V. Importance of Drug metabolism
VI.The pharmacological and toxicological significance of drug metabolism
VII.The purpose of drug metabolism studies in drug development
VIII.Factor influencing drug metabolism
IX.The enzyme needed for drug metabolism
X. Result of drug metabolism
XI.Introduction to drug excretion
XII.Routes of drug excretion
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Introduction
• Drug metabolism is the metabolic breakdown of drugs by living
organism,usually through specialized enzymatic systems. More
generally,xenobiotic metabolism (from the Greek xenos stranger and
biotic related to living beings) is the set of metabolic pathways that
modify the chemical structure of xenobiotics,which are compounds
foreign to an organisms normal biochemistry,such as any drug or
poison.
• Or, briefly-The biochemical alteration of drugs inside the body is
called metabolism/biotransformation.
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Aims and objects of drug metabolism
1.To make drugs:
-Highly polar compound.
-More water soluble.
-More lipid insoluble(less lipid insoluble)
2.To promote excretion of drugs.
3.To convert pharmacologically inactive prodrugs into
pharmacologically active drugs in vivo.
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#Process of drug metabolism
The process of drug metabolism requires two phases of reaction:
1.Phase1 reaction.(Non synthetic phase)
This involves a change in drug molecule.It involves oxidation,reduction or
hydrolysis.This may result in activation,change or inactivation of drug.
2.Phase2 reaction.(Synthetic phase)
It involves formation of conjugates with drug or its metabolites formed in phase1
reaction.The conjugate is formed with an endogenous substance such as
carbohydrates and amino acids.
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Importance of drug metabolism
Termination of drug action
Activation of prodrug
Bio activation and toxication
Teratogenesis
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The pharmacological and toxicological significance
of drug metabolism:
The pharmacokinetic sphere has immense significance
in drug development because the ADME(absorption,
distribution, metabolism and elimination) studies which it
involves generate information on:
1. The chemical natures of molecules produced within
the target organism to which specific target sites will
be exposed.
2. The quantities and concentration time courses of
these various compounds (parent and metabolites).
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The purpose of drug metabolism studies in
drug development:
The objectives of the various pharmacokinetic studies which are
performed during the course of drug development may be
summarized briefly as follows:
(1)Assessment of drug levels and kinetics in blood ,body fluid and
tissues.
(2)The rate and extent of absorption at different dose levels.
(3)The distribution of the drug and its metabolites in
tissues,organs,and body fluids at different dose levels and after single
and multiple doses.
(4)The pattern and rate of metabolism and excretion at different dose
levels.
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(5)Plasma protein and tissue binding of drug and metabolites at
different dose levels.
(6)Accumulation or retentention of drug not metabolites upon
chronic dosing.
(7)Enzyme induction and inhibition potential of the compound.
(8)Characterisation ,identification and pharmacokinetics of
metabolites.
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Factor influencing drug metabolism
• Age
• Diet
• Genetic variation
• State of health
• Nutritional status
• Gender
• Degree of protein binding
• Species variation
• Substrate competition
• Enzyme induction/inhibition
• Route of drug administration
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Age: Age is an impaired factors because very young and old have impaired
metabolism.The activities of drug metabolizing enzyme varies with age . For infants
and newborn the activities of these enzyme are less than that in adults.
For example: The oxidative metabolism of Tolbutamide is lower in newborn.
Again in older people, both the liver mass and hepatic blood flow decrease.It
decrease the metabolism of drug.
Diet: The enzyme content and activity is altered by a number of dietary components.
Generally
1. Low protien diet decreases and high protein diet increases the drug
metabolizing ability as enzyme synthesis is promoted by protein diet and also raises
the level of amino acids for conjugation with drugs.
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Genetic Variation: Patients vary widely in their response to drugs.Genetic factors can
account for 20 to 95 percent of patient variability. Genetic polymorphisms for many drug
metabolizing enzymes and drug targets(e.g: receptors) have been identified.
State of health: Drug metabolism may depend on histological changes in the liver (acute or
changes in the liver (acute or chronic hepatitis, cirrhosis) but may also depend on their origin(
viral, toxic, or immunological). A number of hepatic diseases have showed effects on drug
metabolism.
Nutritional status: The enzyme content and activity is altered by a number of dietary
components. Generally
1. Low protein diet decreases and high protein diet increases the drug metabolizing ability
as enzyme synthesis is promoted by protein diet and also raises the level of amino acids for
conjugation with drugs.
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2. Fat free diet depresses cytochrome P-450 levels since phospholipids, which are
important components of microsomes become deficient.
3. Dietary deficiency of vitamins like vitamin A,B2,B3,C and E and minerals such as Fe
, Ca, Mg, Zn retard the metabolic activity of enzymes.
Gender: Rate of drug metabolism also depend on the sex of the patient. In human
women metabolize benzodiazepines slowly than men. Again several studies show
that, women taking contraceptive pills metabolize a number of drug at a slow
rate.In animals, a marked difference is observed between male and female rats .
Adult male rat metabolize some drugs more quickly than adult female rat.
Degree of protein binding: Increase the degree of protein binding, decrease the rate
of metabolism
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Species variation: Species difference have been observed in both phase-I and
Phase-II reactions. In phase-I reactions, both qualitative and quantitative
variations in enzyme and their activity have been observed
Human liver contains less cytochrome P-450 per gram of tissue than do the liver
of other species.For example rat liver contain approximately 30 to 50 nmol/g of
cytochrome P-450, where as human liver contains 10 to 20 nmol/g.
Substrate competition: A drug may inhibit the biotransformation of another drug
when administered simultaneously . e.g. SKF-525A inhibits the microsomal
enzymes that metabolize a large variety of drugs.
Enzyme induction: Phenobarbitone, phenytoin, steroid, Meprobamate may induce
hepatic microsomal enzyme . This enhance metabolism of some drugs
e.g.Anticougulants, oral hypoglycaemic agents.
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##The enzymes needed for drug metabolism-
• The drug metabolizing enzymes are divided into two types-
Microsomal enzymes:
Cytochrome P-450
CytochromeP-450 reductase
Flavin enzyme
Molecular oxygen
Used in:
• Oxidation reaction
• Reduction reaction
• Hydrolysis reaction
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Result of drug metabolism
• The results of drug metabolism are the conversion of:
1. Pharmacologically active drug into inactive metabolites.
Morphine:Morphine glucuronide
2.Pharmacologically active drugs into another active metabolites:
Aspirin:Salicylic acid
Phenacetin:Paracetamol
Codeine:Morphine
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3.Pharmacologically inactive drugs into active drugs:
Prontosil:Sulfonamide
Levodopa:Dopamine
Talampicillin:Ampicillin
4.More toxic drugs into less toxic metabolites:
Phenacetin:Acetaminophen
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Routes of drug excretion
1.Main routes or renal routes of drug excretion:
Kidney or renal excretion
2.Other or non renal routes of excretion:
Urine
Faeces
Exhaled air
Saliva & sweat
Milk
Liver
Hair and nails
