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BIOTRANSFORMATION
By dr. shah murad
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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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