bio transformation 1

8/14/2019 Bio Transformation 1

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BIOTRANSFORMATION

By dr. shah murad

[email protected]


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Biotransformation or drug

metabolism

Chemical altera tio n o f th e drug inthe body Drugs taken should be changed

from their original form to more

excretable form, by biological

processes of human body METABOLISM includes,Anabolism

and Catabolism(breakdown of

some compounds and synthesis of


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It is needed to render non

polar(lipid soluble) compounds

POLAR(lipid insoluble) so thatthey are not reabsorbed in the

renal tubules and are excreted.

Most hydrophylic drugs likestreptomycin,neostigmine are

not biotransformed and are

excreted unchanged.


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Mechanisms which metabolize

drugs(essentially foreign

substances) have developed toprotect the body from ingested

toxins.


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The primary site for drug

metabolism is liver; others are

kidney,intestine,lungs andplasma.

Metabolism of drugs may lead

to INACTIVATIONACTIVEMETABOLITE FROM ACTIVE

DRUG orACTIVATION OF

INACTIVE DRUG


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DRUG MAY BE:

In active form

In inactive form

In toxic form


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Drug may be:

As raw material

May be synthetic form

May be semi-synthetic form

Taken as nutrition only

Taken as essential bodycompounds, like VITAMINS


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Why metabolism of drug is

essential???

All forms of drug should be changed fromone to another form.because

2. It may require to be changed from

inactive to active form for itspharmacodynamic action

3. If it is active, it may require to bechanged chemically for its requiredtherapeutic action

4. If it is in more active(toxic)form,it isnecessary to be changed chemically forits therapeutic action with less toxiceffects


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Drug is BASICALLY:

Recognized as Antigen for the

body tissue

Soit should be changed (by

metabolism) TO BE

RECOGNISED BY BODYTISSUES for ITS THERAPEUTIC

ACTION


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Biotransformation is divided

in 2 PHASES

PHASE I REACTIONS(nonsynthetic reactions)

PHASE II REACTIONS(syntheticor conjugation reactions)


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Phase I reaction

Phase I reactions usuallyconvert the parent drug to a

more polar metabolite byintroducing or unmasking afunctional group like OH,-NH2 ,-SH

Often these metabolites areinactive, although in some

cases activity is only modified


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If phase I metabolites are

sufficiently polar, they may be

readily excreted.

However ,many phase I

products are not eliminated

rapidly and undergo PHASE II

reactions


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Phase II reaction

Endogenous substrate like

glucuronic acid, sulfuric acid,

acetic acid, or an amino acidcombines with the newly

incorporated functional group to

form a highly polar conjugate. These are known as synthetic

reactions.


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ABSORPTION >> METABOLISM >> ELIMINATION

DRUG >>>>>phase Iphase II >> >> >>Elimination

Drug{drug metabolites with modified activity/inactive drug metabolite>>conjugate>>Elimination

Drug >> >> >> >> >> >> >> >> >> >> >> Elimination

Lipophobic material.......Hydrophobic material>> > >> >> >> >>Elimination


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Phase II>>>>Phase

I>>>>>Elimination In some cases the parent drug mayalready possess a functional group

that may form a conjugate directly.For

example HYDRAZIDE part ofISONIAZID is known to form an N-

acetyl conjugate in a phase II

reaction.This conjugate is then asubstrate for a >>>>>>>phase I

reaction(hydrolysis) to ISONICOTINIC

ACID


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Active metabolite

Trichloroethanol

paracetamol

Oxyphenylbutazone

Oxazepam

Digoxin

Desipramine

NortriptylineMorphine

Canrenone

E 3/74

Active drug

Chloralhydrate>>

Phenacetin

Phenylbutazone

Diazepam

Digitoxin>>


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Dopamine

Enalaprilat

Alfa-methyl ne

Progl triazine

Prednisolone

Ampicillin5-

aminosalicylic

a

Fluorouridine

Levodopa

Enalapril

Alfa-methyldopa

Proguanil

PrednisoneBecampicillin

Sulfasalazine

Fluorouracil

Acive formProdrug


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NONSYNTHETIC(phase

I)reactions

Oxidation

Reduction

Hydrolysis

Cyclization

Decyclization


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The most important single group ofreactions is the oxidations,inparticular those undertaken by theso-called MIXEDFUNCTION(microsomal)OXIDASESwhich are capable of metabolising awide variety of compounds.

The most important enzyme is ahaem,cytochrome P450,which takepart in a process whereby molecularoxygen is bound and incorporated

into the drug molecule,so forming a


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Oxidation

It involves addition of oxygen/-ve

charged radical or removal of H/+ve

charged radical.

Most important reactions for drugbiotransformation>>>>>hydroxylation,

oxygenation at C,N or S atoms,N or O-

dealkylation,oxidative


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In many cases the initial insertion of O2

atom into the drug molecule produces

short lived highly reactive

quinone/epoxide/superoxide intermediates

which then convert to more stable

compounds.


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Oxidative reactions are mostly carried outby a group of mono-oxygenases in theLIVER,which in the final step involve a

cytochrome P-450haemoprotein,NADPH,Cytochrome P-450

reductase and O2. More than 100 cytochrome P-450 isoenzymes

differing in their affinity for varioussubstrates(drugs),have been identified.

An isoenzyme is one of a group of enzymesthat catalyse the same reaction but differ inprotein structure.


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The relative amount of different

cytochrome P-450s differs

among species and amongindividuals of the same species.

These differences largely

account for markedinterspecies and interindividual

differences in rate of

metabolism of drugs.


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CYP2C8/9: are important in the

biotransformation of >15 commonly

used drugs including

phenytoin and

warfarin which are narrow safety

margin drugs.


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CYP2C19: metabolizes >12 frequently

used drugs includingOMEPERAZOLE,lansoprazole.

CYP3A4/5: is responsible formetabolism of largest

number(>50%)of drugs.in addition to

liver,these isoforms are present inst

C 2 6


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CYP2D6: this is the next most

important CYP isoform which

metabolizes nearly 20% drugsincluding tri-cyclic

antidepressants,neuroleptics,antiarrh

ythmics,beta blockers andopiates.INHIBITION OF THIS ENZYME

BY quinidine RESULTS IN FAILURE OF

CONVERSION OF CODEINE TOMORPHINE>analgesic effect

of codeine is lost.


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CYP2E1:it catalyses formation

of minor metabolites of few

drugs,notably the hepatotoxicN-acetyl benzoquinoneimine

from PARACETAMOL.chronic

alcoholism induces thisisoenzyme.It also catalyses a

reaction involved in the

metabolism of

alcohol oestradiol eth n loestra


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BARBITURATES,phenothiazines,steroi

ds,benzodiazepines,theophylline and

many other drugs are oxidized in thisway.

Some other drugs eg;adrenaline,alcohol,mercaptopurine

are oxidized by mitochondrial or

cytoplasmic enzymes.


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Reduction

Reductive reactions are much less commonthan oxidations but some are important.forexample WARFARIN is inactivated byconversion of a ketone to a hydroxyl groupby CYP2A6.

This reaction is the conversion of oxidationand involves CYP enzymes working in theopposite direction.

Drugs primarily reduced arechloralhydrate,chloramphenicol,halothene.


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Hydrolysis

This is cleavage of drug molecule by takingup a molecule of water.

ESTER+H2O (esterase) Acid + Alcohol

Similarly amides and polypeptides arehydrolysed by amidases and peptidases.

Hydrolysis occurs in liver,intestine,plasmaand other tissues.EXAMPLES are>>>choline

esters,procaine,lidocaine,procainamide,pethidine,oxytocin.

These reactions do not involve hepaticmicrosomal enzymes.


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Cyclization

This is formation of RING

STRUCTURE,from a straight

chain compound;eg.proguanil. Main site of biotransformation is

liver and plasma.


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Decyclization

This is opening up of ring structure of

the cyclic drug molecule,eg.

Barbiturates,phenytoin.

This is generally a minor pathway of

metabolism.


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Some Phase I reactions

O XI DATI VE REACTI O NS:Hydroxylation(phenytoin,tolbutamide,ph

enobarbital,cortisol,phenylbutazone)Al

kylation(imipramine,codeine,6-

methylthiopurine)Deamination(amphet

amine,diazepam)Desulphuration(parat

hion)Sulphoxidation(chlorpromazine)Non-microsomal oxidation(ethyl

alcohol)

N-oxidation(acetaminophen,nicotine)5-


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P-450 independent

OXIDATIONS Amine oxidation >>> epinephrine

Dehydrogenation >>> ethanol,chloral

hydrate


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REDU CTIVE REACTI O N S:Chloramphenicol,clonazepam,dan

trolene,naloxone

H YD R O LYTIC REACTI O N S :Enalapril>>>>>enalaprelat

Procaine>>>>>procainamide

N h ti it f d


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Non-hepatic sites for drug

metabolism

Suxamethonium,procaine >> in

PLASMA

Prostanoids >> in LUNGS

Tyramine >> in INTESTINE


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G ti f t hi h


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Genetic factors which

influence drug metabolism Hydrolysis of esters----- succinylcholine is an ester

that is metabolized by plasma cholinesterase(pseudo-cholinesterase OR butyrylcholinestrase).

In most individuals ,this process occurs very

rapidly,and a single dose of this neuromuscularblocking drug has a duration of action of about 5minutes.

Approximately 1 person in 2500 has an abnormalform of this enzyme that metabolizes

succinylcholine and similar esters much moreslowly.In such persons,the neuromuscularparalysis produced by a single dose ofsuccinylcholine may last in many hours.


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Acetylation of amines

(SLOW & FAST ACETYLATORS)

Isiniazid & some other amines such ashydralazine and procainamide aremetabolized by N-acetylation.Persons

defficient in acetylation capacity,calledSLOW ACETYLATORS may have prolongedor toxic responses to normal doses of thesedrugs.

Slow acetylators constitute about 50% ofwhite and african-american persons in theUS and a much smaller fraction of asian andin Eskimos populations.

The slow acetylation trait is inherited as an

AUTOSOMAL RECESSIVE gene.


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Phase II reactions

If a drug molecule has a suitable handle(eg; a hydroxyl,thiol or amino group),eitherin the parent molecule or in a product

resulting from phase I metabolism,it issusceptible to conjugation,ie. Attachmentof a substituent group.

The resulting conjugate is almost alwayspharmacologically inactive and less lipid

soluble than its precursor and is excretedin urine or bile.


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The groups most often involved inconjugate formation areglucuronyl,sulfate,methyl,acetyl,glycyl andglutathione.

Glucuronide formation involves theformation of a high-energy phosphatecompound,uridine diphosphate (UDP)glucuronic acid(UDPGA),from which

glucuronic acid is transferred to anelectron-rich atom (N, O,or S) on thesubstrate ,forming an amide,ester or thiolbond.


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Uridine diphosphate(UDP) glucuronyl

transferase,which catalyses phase 2

reactions,has very broad substratespecificity embracing many drugs and

other foreign molecules.

Several important endogenoussubstances,such as bilirubin and

adrenal corticosteroids,are also

conjugated by the same system.


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Acetylation and methylation

reactions occur with acetyl-CoA

and S-adenosylmethionine,respectively,acting

as the donor compounds.


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In the liver,the enzymes of phase II

reaction are located intracellularly

and mostly attached to the smoothendoplasmic reticulum and are often

called microsomal enzymes >>>>>in

order to reach these enzymes drugs

must cross the hepatocyte membrane.

Non-ionized drug is therefore resistantto hepatic degradation(unless there is

a specific active transport

Microsomal enzymes constitute a


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Microsomal enzymes constitute a

mixed function oxidase system and

require NADPH and oxygen.

It involves an electrontransfer chain

consisting of threecomponents>>>>They are a flavo-

protein the NADPH-cytochrome-C(P-

450) reductase, a hemoprotein-thecytochrome P-450,and a lipid

component-the phosphotidylcholine.

After xenobiotics undergo enzymatic


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After xenobiotics undergo enzymatic

phase I metabolism

reactions>>>>some reactive groups

may still persist and are nowamenable to the process of

conjugation(phase II reaction)

involving the chemical combination ofthis reactive group with a molecule

eg,glucuronic acid

,glycine,sulphate,acetate Such a conjugate is essentially

pharmacologically inert and less lipid

soluble (more water soluble) as


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Examples of phase II

reaction GLYCIN E CON JUG ATIO N >>> acetyl salicylic acid >>> salicylicacid

Sulphate conjugation >>> acetaminophen >>>acetaminophen sulphate

Acetylating >>> isoniazid >>> acetylatedisoniazid

Methylation >>> nor-epinephrine >>> nor-metanephrine


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bio transformation 1

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