BIOTRANSFORMATION.pptx

Dr. Devesh Pandey
MBBS, MD (Pharamcology)
Professor
Dr. Devesh Classes (devesh3747@gmail.com)

INTRODUCTION
 It means enzyme catalysed biochemical
transformation of drugs within living organisms.
 Biotransformation is a major mechanism for drug
elimination.
 Site- Liver (mainly), kidney, intestine, adrenal cortex,
lungs, placenta, skin.

PROCESS OF
BIOTRANSFORMATION
 Form --- less lipid soluble metabolites
Not reabsorbed from renal tubules
Finally excreted.

Consequences of Biotransformation
1. Active drug Inactive metabolite
e.g. Phenobarbitone Hydroxyphenobarbitone
Ibuprofen, paracetamol, lidocaine.
2. Inactive (Prodrug) Active metabolite
e.g. L-dopa Dopamine
Parathion Paraxon
Talampicillin Ampicillin
Enalapril Enalaprilat

3. Active drug Active metabolite
e.g. Digitoxin Digoxin
Diazepam Oxazepam
Amitriptyline Nortriptyline
Imipramine Des-imipramine
Codeine Morphine

FIRST PASS METABOLISM
 Oral drug > GIT > Portal system > Systemic circulation.
 First pass effect means drug metabolism occurring before drug
enters the systemic circulation.
 Result - decreased bioavailability of drug, diminished
therapeutic response.
 It is bypassed if drug given parenterally ( IV, sublingually).
 If drug metabolites which are active after oral route
significance of first pass decreases as in liver disease oral
bioavailability of of drug might go much higher.

Chemical pathways of drug biotransformation
(A)NON SYNTHETIC/ FUNCTIONALIZATION/ PHASE 1 REACTIONS-
 Drugs diminished to a smaller polar/ nonpolar metabolite by
introduction of a new group (Degradation reactions)
 Reaction are mainly microsomal.
 Include oxidation, reduction or hydrolysis reactions.
 Metabolite formed may be active or inactive.
(B) SYNTHETIC/ PHASE 2 REACTIONS/ CONJUGATION-
 Catalyzed by microsomal, mitochondrial or cytoplasmic enzymes
 Metabolite formed usually Polar, water soluble and mostly
inactive.
 Some drugs containing reactive groups capable of being
conjugated phase 2 without undergoing phase 1 reaction.

THE DRUG METABOLISING ENZYMES
(1)Microsomal Enzymes-
 Located primarily on the smooth-surface endoplasmic
reticulum of the liver also in intestinal mucosa, lungs
and in kidney.
 The principal enzymes- Mixed function Oxidases
(MFOS) or cytochrome P-450 (haemoproteins).
 Glucuronyl transferase is also microsomal enzyme.
 The microsomal enzymes are non-specific in action.

 Microsomal enzymes are concerned primarily with phase I
reaction-oxidation,reduction and hydrolysis-and also phase
II glucuronyl coniugations.
 Specific forms of cytochrome P-450 (CYP) enzymes have
been classified
 e.g. CYP2D6 is the cytochrome P-450 enzyme belonging
to family 2, subfamily D (amino acid sequence) with gene
number 6 ( specific isoenzyme).

 CYP3A4 and CYP3A5:
 Nearly 50% of xenobiotics (drugs and other chemical
substances) are metabolised by these CYPs.
 Barbiturates (sedative-hypnotics),carbamazepine and
phenytoin (anticonvulsants) and rifampicin (antitubercular
drug) are their inducers.
 While erythromycin and clarithromycin (macrolide
group of antibiotics), ketoconazole and fluconazole
(antifungal drugs), yerapamil and diltiazem (Ca channel
blockers), ritonavir (antiretroviral drug against AIDS), act
as their inhibitors.
 CYP3A5 is usually less active than CYP3A4.

CYP2D6-
 Inhibitora are- Quinidine, fluoxetine.
 Inducers are- rare
 Greater genetic polymorphism.
CYD2C8 and CYP2C9-
 E.g. phenytoin and warfarin
 Inducers are- Barbiturates and rifampicin

(2) Non-microsomal enzymes-
 Enzymes of non-microsomal origin.
 Site- cytoplasm, mitochondria of hepatic cells (and
other tissues) and in plasma.
 Examples- Monoamine oxidase, esterases, amidases,
transferases and conjugages.
 Reactions catalysed- all phase II reactions (except
glucuronide conjugation), certain oxidation, reductions.
 Non-inducible, can be inhibited.

PHASE 1 REACTIONS
(A) OXIDATIONS-
(1) Microsomal oxidations-(CYP dependent)
 Aromatic Hydroxylations-
e.g. Phenobarbitone to p-hydroxyphenobarbitone.
phenytoin, propranolol, amphetamine, warfarin.
 Aliphatic Hydroxylation-
e.g. Pentobarbitone to hydroxypentobarbitone.
digitoxin, ibuprofen.

 N-, O- and S-Dealkylation-
e.g. Amitriptyline to nortriptyline
codeine to morphine
 Deamination-
e.g. Amphetamine to phenylacetone derivative.
 Desulferisation-
e.g. Parathion to paraxon.

(2) Non-microsomal Oxidations-
Mitochondrial Oxidations-
e.g. catecholamine like epinephrine to vinyl-mandelic acid
by monoamine oxidase.
Cytoplasmic oxidation (dehydrogenation)-
e.g. alcohal to acetaldehyde by alc. Dehydrogenase.
Plasma Oxidative process-
e.g. oxidative deamination of histamine.

(B) REDUCTIONS-
(1) Microsomal reductions-
 Nitro Reduction-
e.g. Chloramphenicol to its arylamines.
 Azo Reduction-
e.g. Prontosil(prodrug) to sulfanilamide.
 Keto Reduction-
e.g. cortisone to hydroxycortisone.
(2) Non-microsomal Reductions-
e.g. Chloral hydrate to trichloroethanol.

(C) Hydrolysis-
(1) Microsomal Hydrolysis-
 Rarely microsomal, except hydrolysis of pethidine to
pethidinic (meperidinic) acid and hydrolysis of lidocaine
by esterase.
(2) Non-microsomal Hydrolysis-
 Mainly for esters and amides.
 Procaine to PABA by plasma choline esterase;
atropine to tropic acid; hydrolysis of B-lactam ring of
penicillin-G and hydrolysis of procainamide by
amidases

PHASE 2 REACTIONS
CONJUGATIONS
1. Microsomal Conjugations-
 Glucuronide Conjugation- (microsomal)
 Parent drugs or their phase I metabolites undergo
coniugation reaction with uridine diphosphate glucuronic
acid (UDPGA) catalysed by microsomal UDP-glucuronyl
transferase enzymes.
 Yield drug-glucuronide conjugates which are polar, readily
excreted, often inactive (except morphine glucuronide
which is active).
 E.g. morphine, paracetamol, aspirin, chloramphenicol,
diazepam, sulfonamides, endogenous substance like
bilirubin.

2. Non-microsomal Conjugation-
N-Acetyl Conjugation (in cytosol)-
 Catalysed by N-acetyltransferase, acetyl coenzyme-A as a
cofactor.
 E.g. isoniazid, PAS, dapsone, sulfonamides, procainamide
and histamine.
Sulfate Conjugation (in cytosol)-
 Catalysed by enzymes called sulfotransferases.
 Sulfate conjugates highly polar, readily excreted in urine.
 E.g. aspirin, methyldopa, paracetamol,
hydroxycoumarins, corticosteroids and chloramphenicol.

Amino Acid Conjugation (in mitochondria)-
 e.g., aspirin, benzoic acid, nicotinic acid and deoxycholic
acid) couple with glycine or glutamine in presence of
AcCoA-glycine transferase enzymes.
Methyl Conjugation (in cytosol)-
 Catecholamines (e.g., dopamine and epinephrine), amines
(like histamine).
 Catalysing enzyme- transmethylase while cofactor (methyl
donor) is S-adenosine methionine.
Glutathione conjugation ( Cytoplasm )-
 E.g. ethacrynic acid .

NON-ENZYMATICBIOTRANSFORMATION
(HOFMANNELIMINATION)
 Some drugs like atracurium (skeletal muscle relaxant)
metabolised in the plasma spontaneously through
molecular rearrangement without involvement of any
enzyme.
 Such non-enzymatic biotransformation of drugs is called
Hofmann action.

ENZYME INDUCTION
 Stimulation/induction, although reversible, leads to an
enhanced microsomal enzyme activity.
 Results in accelerated metabolism and consequently
decreased pharmacological response.
 Enzyme induction mostly in liver, also in the intestine,
lung, placenta and kidney, e.g., CYP1A1 isoenzyme is
induced in the lungs of cigarette smokers.
 Enzyme induction requires the synthesis of proteins,
it occurs gradually over a period of 1-2 weeks.

Clinical Relevance of Enzyme Induction
(A) Clinical consequences of increased drug metabolism
include:
 Decreased plasma levels and decreased therapeutic
effect of the co-administered drug,
 Decreased drug effect if its metabolite is
inactive,
 Increased drug activity if its metabolite is active.

Examples of enzyme induction-
i) Unwanted pregnancy even with oral contraceptive pills,
if potent enzyme inducers, Iike phenytoin or rifampicin,
are used concomitantly.
ii) Patients on enzyme-inducing drugs, like barbiturates
need higher doses of oral anticoagulants, like warfarin.
iii) Enzyme inducers, like phenytoin, accelerate metabolism
of vitamin D, leading to osteomalacia (side effect)
iv) Enzyme inducers, like barbiturates, enhance their own
metabolism leading to pharmacokinetic tolerance.

(B) Enzyme induction can lead to drug toxicity-
e.g., ethanol drinkers have more probabilities of
developing hepatotoxicity from paracetamol due to
increased production of N-acetyl-P-benzo-
quinoneimine.
(C)Enzyme induction can used for therapeutic benefits-
e.g., to treat neonatal jaundice.
Phenobarbitone given to the pregnant mother 7-14 days
pror to labour or to the infant soon after birth to induce
foetal hepatic glucuronyl transferase enzyme which
catalyses conjugation of bilirubin to glucuronic acid.
Hence, bilirubin gets conjugated (metabolised) faster and
excreted through bile.

ENZYME INHIBITION
 Drug inhibit the metabolism of another drug.
 Result- increase in the circulating levels of the slowly
metabolised drug and prolongation or potentiation of its
pharmacological effects.
 The enzyme inhibition of hepatic microsomal mixed
function oxidase (MFOS) or of enzymes e.g., xanthine
oxidase, monoamine oxidase and aldehyde
dehydrogenase etc.
 Enzyme inhibition- rapid process, usually reversible,
However, it could be irreversible as in the case of
secobarbital overdoses.

Clinical Relevance of Enzyme Inhibition
(A) Potentially Adverse Consequences-
 Unexpected nausea/vomiting and tremors due to
theophylline with concomitantly administered
chloramphenicol or erythromycin (enzyme
inhibitor).
 Enhanced bleeding tendency with dicumarol when
administered with cimetidine (enzyme inhibitor).

 Severe respiratory depression with morphine
when given with MAOIs (monoamine oxidase
inhibitors).
 Severe ataxia and drowsiness with phenytoin in -
combination with dicumarol or chloramphenicol.
 Precipitation of cardiac arrhythmias with
terfenadine when given with
chloramphenicol or ketoconazole (enzyme inhibitor).

(B) Therapeutically Beneficial Consequences-
Increased accessibilty of l-dopa in brain with carbidopa.
Aversion to alcohal after prior administration of
disulfiram (aldehyde dehydrogenase inhibitor).
Reversal of skeletal muscle paralysis due to d-
tubocurarine by neostigmine (actylcholinsterase
reversible inhibitor).

Examples of Genetic Polymorphism in Drug Metabolism

FACTORS AFFECTING
DRUG METABOLISM
(1) Age-
 Neonates- low microsomal enzyme and glucuronyl
transferase enzyme activity
 Thus neonates predisposed to cyanotic condition, called
'grey baby syndrome' after chloramphenicol, which is
metabolised by glucuronyl conjugation.
 Elderly persons (>60 yurs), have reduced hepatic blood
flow. Hence drugs like propranolol and pethidine exhibit
slow metabolism and increased incidence of toxicity.

(2) Species-
Rabbits metabolise atropine faster than man as
they have high atropine esterase activity in the liver
and plasma.
(3) Race-
Chinese- high alcohol dehydrogenase but low aldehyde
dehydrogenase activity. Hence higher plasma
concentration of aldehyde (headache, palpitation etc.)
after consuming alcohol.
(4) Drug-drug Interactions -
Many drugs affect rate of metabolism of other
drugs.
This happens due to either enzyme induction
or enzyme inhibition

(5) Nutrition and Diet-
Diet rich in protein and low in carbohydrate enhances
rate of metabolism of many drugs.
Diets very poor in protein and rich in carbohydrate slow
down rate of drug metabolism (e.g., starvation leads to
enzyme inhibition).
(6) Disease-
Activity of hepatic cytochrome P-450 enzymes impaired
in pathological states, like viral hepatitis, alcoholic
hepatitis, liver cirrhosis, hepatocellular carcinoma and
heavy metal poisoning.
Hypothyroidism decreases the metabolism
of digoxin, methimazole.

CONCLUSION
 Biotransformation is chemical alteration of drugs which
renders non polar lipid soluble compounds polar which are
easily excreted.
 Liver is the Primary site of Drug metabolism.
 Most common CYP450 enzyme for drug metabolism is
CYP3A4.
 Drug interaction can take place as some drugs can inhibit
or induce the microsomal enzymes thereby increasing
chances of drug toxicity or failure respectively.

THANK YOU….

BIOTRANSFORMATION.pptx

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