drugmetabolism-130121005951-phpapp01

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Drug Metabolism


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METABOLISM OR BIOTRANSFORMATIONThe conversion from one chemical form of a substance to another.

The term metabolism is commonly used probably because products of drugtransformation are called metabolites .

Metabolism is an essential pharmacokinetic process, which renders lipid soluble andnon-polar compounds to water soluble and polar compounds so that they areexcreted by various processes.

This is because only water-soluble substances undergo excretion, whereas lipidsoluble substances are passively reabsorbed from renal or extra renal excretory sitesinto the blood by virtue of their lipophilicity.

Metabolism is a necessary biological process that limits the life of a substance in thebody.

Biotransformation : It is a specific term used for chemical transformation ofxenobiotics in the body/living organism.

a series of enzyme-catalyzed processes that alters the physiochemical properties offoreign chemicals (drug/xenobiotics) from those that favor absorption across biologicalmembranes ( lipophilicity) to those favoring elimination in urine or bile (hydrophilicity )


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Functions of Biotransformation

It causes conversion of anactive drug to inactive or

less active metabolite(s)called as pharmacologicalinactivation .

It causes conversion of anactive to more activemetabolite(s) called asbioactivation ortoxicological activation .

It causes conversion of aninactive to more activetoxic metabolite(s) calledas lethal synthesis


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It causes conversion of aninactive drug (pro-drug) toactive metabolite(s) calledas pharmacologicalactivation

It causes conversion of anactive drug to equally active

metabolite(s) ( no change inpharmacological activity)

It causes conversion of anactive drug to active

metabolite(s) havingentirely differentpharmacological activity(change in pharmacologicalactivity)

Functions of Biotransformation contd


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Site/Organs of drug metabolism

The major site of drug metabolism is the liver(microsomal enzyme systems of hepatocytes)

Secondary organs of biotransformation kidney (proximal tubule) lungs (type II cells)

testes (Sertoli cells) skin (epithelial cells); plasma. nervous tissue

(brain); intestines


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Sites of Biotransformation contdLiver

The primary site for metabolism of almost all drugs because it is relativelyrich in a large variety of metabolising enzymes.

Metabolism by organs other than liver ( called as extra-hepatic metabolism )is of lesser importance because lower level of metabolising enzymes ispresent in such tissues.

Within a given cell, most drug metabolising activity is found in the smooth

endoplasmic reticulum and the cytoso l. Drug metabolism can also occur in mitochondria, nuclear envelope andplasma membrane.

A few drugs are also metabolised by non-enzymatic means called as non-

enzymatic metabolism.

For example, atracurium, a neuromuscular blocking drug, is inactivated inplasma by spontaneous non-enzymatic degradation (Hoffman elimination)in addition to that by pseudocholinesterase enzyme.


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Subcellular Locations of Metabolizing Enzymes ENDOPLASMIC RETICULUM (microsomes): the primary location for the

metabolizingenzymes. (a) Phase I: cytochrome P450 , flavin-containing monooxygenase, aldehydeoxidase,

carboxylesterase, epoxide hydrolase, prostaglandin synthase, esterase. (b) Phase II uridine diphosphate-glucuronosyltransferase, glutathione S-

transferase, amino acid conjugating enzymes. CYTOSOL(the soluble fraction of the cytoplasm): many water-soluble enzymes. (a) Phase I: alcohol dehydrogenase, aldehyde reductase, aldehyde dehydrogenase,

epoxide hydrolase, esterase. (b) Phase 11: sulfotransferase, glutathione S-transferase, N-acetyl transferase,

catechol 0-methyl transferase, amino acid conjugating enzymes.

MITOCHONDRIA.

(a) Phase I: monoamine oxidase, aldehyde dehydrogenase, cytochrome P450. (b) Phase II: N-acetyl transferase, amino acid conjugating enzymes. LYSOSOMES.Phase I: peptidase. NUCLEUS. Phase II: uridine diphosphate-glucuronosyltransferase (nuclear membrane of

enterocytes).


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Drug Metabolising Enzymes

A number of enzymes in animals are capable of metabolisingdrugs. These enzymes are located mainly in the liver, but mayalso be present in other organs like lungs, kidneys, intestine,brain, plasma, etc.

Majority of drugs are acted upon by relatively non-specificenzymes, which are directed to types of molecules rather thanto specific drugs.

The drug metabolising enzymes can be broadly divided into twogroups: microsomal and non-microsomal enzymes.


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Microsomal enzymes : The endoplasmic reticulum (especiallysmooth endoplasmic reticulum) of liver and other tissues

contain a large variety of enzymes, together called microsomalenzymes

(microsomes are minute spherical vesicles derived fromendoplasmic reticulum after disruption of cells bycentrifugation, enzymes present in microsomes are calledmicrosomal enzymes).

They catalyse glucuronide conjugation, most oxidative

reactions, and some reductive and hydrolytic reactions.

The monooxygenases, glucuronyl transferase, etc areimportant microsomal enzymes.


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Non-microsomal enzymes : Enzymes occurring inorganelles/sites other than endoplasmic reticulum(microsomes) are called non-microsomal enzymes.

These are usually present in the cytoplasm, mitochondria, etc.and occur mainly in the liver, Gl tract, plasma and other tissues.

They are usually non-specific enzymes that catalyse fewoxidative reactions, a number of reductive and hydrolyticreactions, and all conjugative reactions other thanglucuronidation.

None of the non-microsomal enzymes involved in drugbiotransformation is known to be inducible.


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Hepatic microsomal enzymes(oxidation, conjugation)

Extrahepatic microsomal enzymes(oxidation, conjugation)

Hepatic non-microsomal enzymes(acetylation, sulfation,GSH,alcohol/aldehyde dehydrogenase,hydrolysis, ox/red)

Drug Metabolism


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Factors Affecting Drug Metabolism

1. Species differences : eg in phenylbutazone, procaine andbarbiturates.

2. Genetic differences variation exist with species3. Age of animal feeble in fetus,aged, newborn.

4.sex: under the influence of sex hormones.5. Nutrition: starvation and malnutrition6. Patholigical conditions: Liver/Kidney dysfunction


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Phase I metabolism is sometimes called afunctionalization reaction ,

Results in the introduction of newhydrophilic functional groups to compounds.

Function: introduction (or unveiling) offunctional group(s) such as OH, NH2, SH,

COOH into the compounds. Reaction types: oxidation, reduction, and

hydrolysis

Enzymes: Oxygenases and oxidases: Cytochrome P450 (P450

or CYP), flavincontaining monooxygenase (FMO), peroxidase, monoamine

oxidase(MAO), alcohol dehydrogenase, aldehydedehydrogenase, and xanthine 0xidase. Reductase:Aldo-keto reductase and quinone reductase.

Hydrolytic enzymes : esterase, amidase, aldehydeoxidase, and alkylhydrazine

oxidase. Enzymes that scavenge reduced oxygen:

Superoxide dismutases, catalase, glutathione peroxidase, epoxide hydrolase, y-

glutamyl transferase, dipeptidase, and cysteine conjugate -lyase

Phase II metabolism includes what are knownas conjugation reactions .

Generally, the conjugation reaction withendogenous substrates occurs on themetabolite( s) of the parent compound afterphase I metabolism; however, in some cases,the parent compound itself can be subject tophase II metabolism.

Function: conjugation (or derivatization) offunctional groups of a compound or itsmetabolite(s) with endogenous substrates.

Reaction types : glucuronidation, sulfation,glutathione-conjugation, Nacetylation,methylation and conjugation with amino acids(e.g., glycine, taurine, glutamic acid).

Enzymes: Uridine diphosphate-Glucuronosyltransferase(UDPGT): sulfotransferase (ST), N-acetyltransferase,glutathione S-transferase (GST),methyl transferase, andamino acid conjugating enzymes.

Glucuronidation by uridine diphosphate-glucuronosyltransferase; Sulfation by sulfotransferase

3. Acetylation by N-acetyltransferase; Glutathioneconjugation by glutathione S-transferase;. Methylation by

methyl transferase; Amino acid conjugation


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PHASE I BIOTRANSFORMATION

Oxidation

Oxidation by cytochrome P450 isozymes (microsomal mixed-functionoxidases).

Oxidation by enzymes other than cytochrome P450s most of these (a) oxidation of alcohol by alcohol dehydrogenase, (b) oxidation of aldehyde by aldehyde dehydrogenase, (c) N-dealkylation by monoamineoxidase.


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Phase I Reactions Oxidation : Oxidative reactions are most important metabolic reactions, as

energy in animals is derived by oxidative combustion of organicmolecules containing carbon and hydrogen atoms.

The oxidative reactions are important for drugs because they

increase hydrophilicity of drugs by introducing polar functionalgroups such as -OH.

Oxidation of drugs is non-specifically catalysed by a number ofenzymes located primarily in the microsomes. Some of theoxidation reactions are also catalysed by non-microsomal enzymes(e.g., aldehyde dehydrogenase, xanthine oxidase and monoamineoxidase).


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The most important group of oxidative enzymes are microsomalmonooxygcnases or mixed function oxidases (MFO).

These enzymes are located mainly in the hepatic endoplasmicreticulum and require both molecular oxygen (0 2) and reducingNADPH to effect the chemical reaction.

Mixed function oxidase name was proposed in order tocharacterise the mixed function of the oxygen molecule, which isessentially required by a number of enzymes located in themicrosomes.


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The term monooxygenses for the enzymes was proposed as theyincorporate only one atom of molecular oxygen into the organic substratewith concomitant reduction of the second oxygen atom to water.

The overall stoichiometry of the reaction involving the substrate RH whichyields the product ROH, is given by the following reaction:

MFORH+02+NADPH+H+ ---------------- R0H+H20+NADP+

The most important component of mixed function oxidases is thecytochrome P-450 because it binds to the substrate and activates oxygen.

The wide distribution of cytochrome P-450 containing MFOs in varyingorgans makes it the most important group of enzymes involved in thebiotransformation of drugs.


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PHASE I ENZYMESCytochrome P450

Monooxygenase(Cytochrome P450, P450,or CYP)

Flavin-ContainingMonooxygenase (FMO)

Esterase Alcohol Dehydrogenase

(ADH)

AldehydeDehydrogenase (ALDH) Monoamine Oxidase

(MAO)

PHASE II ENZYMES Uridine Diphosphate-

Glucuronosyltransferase(UDPGT) Sulfotransferase (ST) N-Acetyltransferase (NAT)

Glutathione S-Transferase(GST)

Methyl Transferase Amino Acid Conjugation


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The cytochrome P-450 ENZYMES

Superfamily of haem-thiolate proteins that are widely distributedacross all living creatures. The name given to this group of proteins because their reducedform binds with carbon monoxide to form a complex, which hasmaximum absorbance at 450 nm. Depending upon the extent of amino acid sequence homology, the

cytochrome P-450 (CYP) enzymes superfamily contains a number ofisoenzymes, the relative amount of which differs among species andamong individuals of the same species. These isoenzymes are grouped into various families designated byArabic numbers 1, 2, 3 ( sequence that are greater than 40% identicalbelong to the same family), each having several subfamiliesdesignated by Capital letter A, B, C, while individual isoenzymes areagain allotted Arabic numbers 1.2,3 (e.g., CYP1A1, CYP1A2, etc.).


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OTHER

36%

CYP2D6

2%

CYP2E1

7%

CYP 2C

17%

CYP 1A212%

CYP 3A4-5

26%

CYP 1A2

14%

CYP 2C9

14%

CYP 2C19

11%

CYP2D6

23%

CYP2E

5%CYP 3A4-5

33%

RELATIVE HEPATIC CONTENTOF CYP ENZYMES

% DRUGS METABOLIZEDBY CYP ENZYMES

ROLE OF CYP ENZYMES IN HEPATIC DRUG METABOLISM In human beings, of the 1000 currently known cytochrome P-450s, about 50 are functionallyactive. These are categorised into 17 families, out of which the isoenzymes CYP3A4 and CYP2D6 carry out biotransformation of largest number of drugs.


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2. Reduction :

ReductionEnzymes responsible for reduction of xenobiotics require NADPH as a cofactor.Substrates for reductive reactions include azo- or nitrocompounds, epoxides,heterocyclic compounds, and halogenated hydrocarbons:

(a) Azo or nitroreduction by cytochrome P450;

(b) Carbonyl (aldehyde or ketone) reduction by aldehyde reductase, aldosereductase, carbonyl reductase, quinone reductase

(c) other reductions including disulfide reduction, sulfoxide reduction, and

reductive dehalogenation.


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The acceptance of one or more electron(s) or their equivalent from anothersubstrate.

Reductive reactions, which usually involve addition of hydrogen to the drug

molecule, occur less frequently than the oxidative reactions.

Biotransformation by reduction is also capable of generating polar functionalgroups such as hydroxy and amino groups , which can undergo further biotrans-formation.

Many reductive reactions are exact opposite of the oxidative reactions(reversible reactions) catalysed cither by the same enzyme (true reversiblereaction) or by different enzymes (apparent reversible reactions).

Such reversible reactions usually lead to conversion of inactive metaboliteinto active drug, thereby delaying drug removal from the body.


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3. Hydrolysis :Esters, amides, hydrazides, and carbamates can be hydrolyzed byvariousenzymes.

The hydrolytic reactions, contrary to oxidative or reductivereactions, do not involve change in the state of oxidation of thesubstrate, but involve the cleavage of drug molecule by taking upa molecule of water.

The hydrolytic enzymes that metabolise drugs are the ones thatact on endogenous substances, and their activity is not confinedto liver as they are found in many other organs like kidneys,

intestine, plasma, etc.

A number of drugs with ester, ether, amide and hydrazidelinkages undergo hydrolysis. Important examples arecholinesters, procaine, procainamide, and pethidine.


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PHASE II REACTIONS

Phase II or conjugation (Latin, conjugatus = yoked together)reactions involve combination of the drug or its phase Imetabolite with an endogenous substance to form a highly polarproduct, which can be efficiently excreted from the body.

In the biotransformation of drugs, such products or metaboliteshave two parts:Exocon, the portion derived from exogenous compound orxenobiotic,

Endocon , the portion derived from endogenous substance.

Conjugation reactions have high energy requirement and theyoften utilise suitable enzymes for the reactions.


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1. Conjugation with glucuronic a./ Glucuronidation

Conjugation with glucuronic acid (glucuronide conjugation or

glucuronidation) is the most common and most importantphase II reaction in vertebrates, except cats and fish.

The biochemical donor (cofactor) of glucuronic acid is uridinediphosphate-D-glucuronicacid (UDPGA) and the reaction iscarried out by enzyme uridine diphosphate-glucuronyltransferase (UDP-giucuronyl transferase; glucuronyltransferase).

Glucuronyl transferase is present in microsomes of mosttissues but liver is the most active site of glucuronidesynthesis.


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Glucuronidation can take place in most body tissues becausethe glucuronic acid donor UDPGA is present in abundant

quantity in body, unlike donors involved in other phase IIreactions.

In cats, there is reduced glucuronyl transferase activity , whilein fish there is deficiency of endogenous glucuronic acid donor.

The limited capacity of this metabolic pathway in cats mayincrease the duration of action, pharmacological response andpotential of toxicity of several lipid-soluble drugs (e.g., aspirin)

in this species.


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A large number of drugs undergo glucuronidation includingmorphine, paracetamol and desipramine. Certain endogenoussubstances such as steroids, bilirubin, catechols and thyroxinealso form glucuronides.

Deconjugaiion process: Occasionally some glucuronideconjugates that are excreted in bile undergo deconjugation

process in the intestine mainly mediated by glucuronidaseenzyme.

This releases free and active drug in the intestine, which may bereabsorbed and undergo entero-hepatic cycling.

Deconjugation is an important process because it often prolongsthe pharmacological effects of drugs and/or produces toxiceffects.


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2. Conjugation with sulphate/ Sulphation :

Conjugation with sulphate (sulphate conjugation,sulphoconjugation orsulphation) is similar to glucuronidationbut is catalysed by non-microsomal enzymes and occurs lesscommonly.

The endogenous donor of the sulphate group is 3'-phosphoadenosine-5'-phosphosulphate (PAPS), and enzymecatalysing the reaction is sulphotransferase


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The conjugates of sulphate are referred to as sulphate esterconjugates or ethereal sulphates. Unlike glucuronideconjugation, sulphoconjugation in mammals is less importantbecause the PAPS donor that transfers sulphate to the substrateis easily depleted.

Capacity for sulphate conjugation is limited in pigs. However

in cats, where glucuronidation is deficient, sulphate conjugationis important. Functional groups capable of forming sulphateconjugates include phenols, alcohols, arylamines, N-hydroxylamines and N-hydroxyamides.

Drugs undergoing sulphate conjugation includechloramphenicol, phenols, and adrenal and sex steroids.


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3. Conjugation with methyl group/ Methylation :

Conjugation with methyl group (methyl conjugation or

methylation) involves transfer of a methyl group (-CH 3) from thecofactor S-adenosyl methionine (SAM) to the acceptor substrateby various methyl transferase enzymes.

Methylation reaction is of lesser importance for drugs, but ismore important for biosynthesis (e.g., adrenaline, melatonin)and | Inactivation (e.g., histamine) of endogenous amines.

Occasionally, the metabolites formed are not polar or water-

soluble and may possess equal or greater activity than theparent compound (e.g., adrenaline synthesised fromnoradrenaline).

4. Conjugation with glutathione and mercapturic acid formation .


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Conjugation with glutathione (glutathione conjugation) and mercapturic acid formationis a minor but important metabolic pathway in animals.

Glutathione (GSH, G=glutathione and SH = active-SH group) is a tripeptide havingglutamic acid, cysteine and glycine.

It has a strong nucleophilic character due to the presence of a -SH (thiol) group in itsstructure. Thus, it conjugates with electrophilic substrates, a number of which arepotentially toxic compounds, and protects the tissues from their adverse effects.

The interaction between the substrate and the GSH is catalysed by enzyme glutathione-S-transferase, which is located in the soluble fraction of liver homogenates.

The glutathione conjugate either due to its high molecular weight is excreted as such inthe bile or is further metabolised to form mercapturic acid conjugate that is excreted in

the urine.


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5. Conjugation with acetyl group/ Acetylation :

Conjugation with acetyl group (acetylation) is an important

metabolic pathway for drugs containing the amino groups.

The cofactor for these reactions is acetyl coenzyme A and theenzymes are non-microsomal N-acetyl transferases, located inthe soluble fraction of cells of various tissues.

Acetylation is not a true detoxification process becauseoccasionally it results in decrease in water solubility of an amin eand. thus, increase in its toxicity (e.g., sulphonamides).


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Acetylation is the primary route of biotransformation ofsulphonamide compounds. Dogs and foxes do not acetylatethe aromatic amino groups due to deficiency of arylamine

acetyltransferase enzyme.

Conjugation with amino acids : Conjugation with amino acidsoccurs to a limited extent in animals because of limitedavailability of amino acids. The most important reactioninvolves conjugation with glycine.

Conjugation with other amino acids like glutamine in man andornithine in birds is also seen.

Examples of drugs forming glycine or glutamine conjugates aresalicylic acid, nicotinic acid and cholic acid .


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Conjugation with thiosulphate : Conjugation with thiosulphate is

an important reaction in the detoxification of cyanide. Conjugationof cyanide ion involves transfer of sulphur atom from thethiosulphate to the cyanide ion in presence of enzyme rhodancseto form inactive thiocyanate.

Thiocyanate formed is much less toxic than the cyanide (truedetoxification) and it is excreted in urine.


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INDUCTION OF METABOLISM Administration of certain xenobiotics sometimes results in a

selective increase in the concentration of metabolizing enzymes inboth phase I and II metabolism, and thereby in their activities Enzyme induction becomes important especially when

polypharmacy involves drugs with narrow therapeutic windows , sincethe induced drug metabolism could result in a significant decrease inits exposure and therapeutic effects.

In addition, enzyme induction may cause toxicity, associated withincreased production of toxic metabolites.Mechanisms of Induction

Stimulation of transcription of genes and/or translation of proteins,and/or stabilization of mRNA and/or enzymes by inducers, resulting inelevated enzyme levels.


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Stimulation of preexisting enzymes resulting in apparentenzyme induction without an increase in enzyme synthesis (thisis more common in vitro than in vivo).

In many cases, the details of the induction mechanisms areunknown.

TWO receptors have been identified for CYPlA1/2 andCYP4A1/2induction:(a) Ah (aromatic hydrocarbon) receptor in cytosol, whichregulates enzyme (CYP1 A1 and 1A2) induction by polycyclicaromatic hydrocarbon (PAH)-type inducers;(b) Peroxisome proliferator activated receptor (PPAR), where

hypolipidemic agents cause peroxisome proliferation in rats(CYP4A1 and 4A2);-humans have low PPAR and show noeffects from hypolipidemic agents.

Characteristics of Induction


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Characteristics of Induction Induction is a function of intact cells and cannot be achieved by treating

isolated cell fractions such as microsomes with inducers. Evaluation of enzyme induction is usually conducted in ex vivo experiments,

ie., treating animals in vivo with potential inducers and measuring enzymeactivities in vitro or in cell-based in vitro preparations such as hepatocytes, liverslices, or cell lines.

Recent studies have demonstrated that primary cultures of hepatocytes canbe used for studying the inducibility of metabolizing enzymes such as P450 undercertain incubation conditions

Enzyme induction is usually inducer-concentration dependent. The extent ofinduction increases as the inducer concentration increases; however, abovecertain values, induction starts to decline.

In general , inducers increase the content of endoplasmic reticulum withinhepatocytes as well as liver weight.

In some cases, an inducer induces enzymes responsible for its ownmetabolism ( so-called autoinduction ) .


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Induction of Drug Metabolising Enzymes

Several drugs and chemicals have ability to increase the drug

metabolising activity of enzymes called as enzyme induction.

These drugs known as enzyme inducers mainly interact with DNA andincrease the synthesis of microsomal enzyme proteins, especiallycytochrome P-450 and glucuronyl transferase.

As a result, there is enhanced metabolism of endogenous substances(e.g., sex steroids) and drugs metabolised by microsomal enzymes.Some drugs (e.g., carbamazepine and rifampicin) may stimulate theirown metabolism, the phenomenon being called as auto-induction orself induction.

Since different c tochrome P450 isoen mes are in ol ed in the


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Since different cytochrome P450 isoenzymes are involved in themetabolism of different drugs, enzyme induction by one drug affectsmetabolism of only those drugs, which are substrate for the inducedisoenzyme.

However, some drugs like Phenobarbitone may affect metabolism of alarge number of drugs because they induce isoenzymes like CYP3A4 andCYP2D6 which act on many drugs.

Enzyme inducers are generally lipid-soluble compounds with relatively longplasma half-lives .

Repeated administration of inducers for a few days (3 to 10 days) is often

required for enzyme induction, and on stoppage of drug administration,the enzymes return to their original value over 1 to 3 weeks.

Non-microsomal enzymes are not known to be induced by any drug orchemical.


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Clinical importance of enzyme induction

It reduces efficacy and potency of drugs metabolised by theseenzymes.

It reduces plasma half-life and duration of action of drugs.

It enhances drug tolerance.

It increases drug toxicity by enhancing concentration ofmetabolite, if metabolite is toxic.

It increases chances of drug interactions.

It alters physiological status of animal due to altered metabolismof endogenous compounds like sex steroids.

Inhibition of Drug Metabolising Enzymes


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Inhibition of Drug Metabolising Enzymes

Contrary to metabolising enzyme induction, several drugs orchemicals have the ability to decrease the drug metabolising activity ofcertain enzymes called as enzyme inhibition.

Enzyme inhibition can be either non-specific of microsomal enzymesor specific of some non-microsomal enzymes (e.g., monoamine oxidase,cholinesterase and aldehyde dehydrogenase).

The inhibition of hepatic microsomal enzymes mainly occurs due toadministration of hepatotoxic agents,

which cause either rise in the rate of enzyme degradation (e.g., carbon

tetrachloride and carbon disulphide) or fall in the rate of enzyme synthesis(e.g., Puromycin and Dactinomycin).

Nutritional deficiency hormonal imbalance or hepatic


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Nutritional deficiency, hormonal imbalance or hepaticdysfunction, etc.also inhibit microsomal enzymes indirectly.

Inhibition of non-microsomal enzymes with specific functionusually results when Structurally similar compounds compete forthe active site on the enzymes.

Such an inhibition is usually rapid (a single dose of inhibitormay be sufficient) and clinically more important than the non-specific microsomal enzyme inhibition.

Enzyme inhibition generally results in depressed metabolism

of drugs.As a result, the plasma hall-life, duration of action, and efficacyas well toxicity of the object drug (whose metabolism has beeninhibited) are significantly enhanced.


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Inducing Agents


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Inducing Agents In general, enzyme inducers are lipophilic at physiological pH and

exhibit relatively long t 1/2 with high accumulation in the liver.

Different classes of enzyme inducers.1. Barbiturates: Phenobarbitone, Phenobarbital.

2. Polycyclic aromatic hydrocarbons (PAH): 3-methylcholanthrene (3-MC),

2,3,7,8,-tetrachlorodibenzo- p-dioxin (TCDD), -naphthoflavone ( -NF).

3. Steroids : Pregnenalone 16- -carbonitrile (PCN), Dexamethasone.

4. Simple hydrocarbons with aliphatic chains: Ethanol (chronic), Acetone,

5. Hypolipidemic agents: Clofibrate, lauric acids.

6. Macrolide antibiotics: T riacetyloleandomycin (TAO).

7. A wide variety of structurally unrelated compounds: e.g., Antipyrine,

Carisoniazid. Bamazepine, Phenytoin, and Rifampicin


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EXTRAHEPATIC METABOLISM


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EXTRAHEPATIC METABOLISM

Most tissues have some metabolic activity; however,quantitatively the liver is by far the most important organ for drugmetabolism.

Important organs for extrahepatic metabolism include theintestine (enterocytes and intestinal microflora), kidney, lung,plasma, blood cells, placenta, skin, and brain.

In general, the extent of metabolism in the major extrahepaticdrug-metabolizing organs such as the small intestine, kidney, andlung is approximately 10 20% of the hepatic metabolism.

Less than 5% of extrahepatic metabolism compared to hepaticmetabolism can be considered low with negligiblepharmacokinetic implications

First Pass Effect/First Pass Metabolism


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First Pass Effect/First Pass Metabolism

First-pass effect (first-pass metabolism or pre-systemic metabolism) may be definedas the loss of drug through biotransformation before it enters systemic circulation.

This may occur during passage of drug for first time (therefore called first-passeffect/metabolism) through intestine or liver after oral administration.

Intestinal first-pass effect: In this type, drugs are metabolised in the gastrointestinaltract by enzymes present in either gut mucosa or gut lumen before they areabsorbed Recent studies have indicated that P450 isoforms such as CYP2C19 and 3A4 inenterocytes might play an important role in the presystemic intestinal metabolism ofdrugs and the large interindividual variability in systemic exposure after oraladministration The cytochrome P450 content of the intestine is about 35% of the hepatic content

in the rabbit, but accounts for only 4% of the hepatic content in the mouse.Cytochrome P450 levels and activities are highest in the duodenum near thepyrolus, and then decrease toward the colon A similar trend in regional activity levels along the intestine has been observed forglucuronide, sulfate, and glutathione conjugating enzymes.

Mi i i h GI l i i d


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Microorganisms present in the GI tract also inactivate some drugs.Such drugs are not suitable by oral administration due to poorbioavailability (e.g., catecholamines).

Hepatic first-pass effect: In this type, drugs are suitably absorbedacross the GI tract and enter portal circulation, but they are rapidlyand significantly metabolised during the first passage through theliver.

(Normally, when a drug is absorbed across GI tract, it first enters theportal vein and passes through liver before it reaches the systemiccirculation).

Such drugs are also not/less suitable by oral administration due totheir poor bioavailability. Examples of drugs undergoing significanthepatic first-pass effect include Propranolol, Lignocaine and Nitro-glycerine.

The rate and extent of first-pass intestinal metabolism of a drug


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after oral administration are dependent on various physiologicalfactors1. Site of absorption : If the absorption site in the intestine is different

from the metabolic site, first-pass intestinal metabolism of a drugmay not be significant.2. Intracellular residence time of drug molecules in enterocytes: Thelonger the drug molecules stay in the enterocytes prior to entering

the mesenteric vein, the more extensive the metabolism.3. Diffusional barrier between splanchnic bed and enterocytes: Thelower the diffusibility of a drug from the enterocytes to themesenteric vein, the longer its residence time.4. Mucosal blood flow: Blood in the splanchnic bed can act as a sinkto carry drug molecules away from the enterocytes, which reducesintracellular residence time of drug in the enterocytes


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Metabolism in Blood Blood contains various proteins and enzymes. As metabolizing enzymes, esterases, including cholinesterase,

arylesterase, and carboxylesterase, have the most significant effectson hydrolysis of compounds with ester, carbamate, or phosphatebonds in blood .

Esterase activity can be found mainly in plasma, with less activity in

red blood cells. Plasma albumin itself may also act as an esterase under certainconditions.

For instance, albumin contributes about 20% of the total hydrolysisof aspirin to salicylic acid in human plasma.

The esterase activity in blood seems to be more extensive in smallanimals such as rats than in large animals and humans. Limited, yetsignificant monoamine oxidase activities can be also found in blood.


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