Dr Anoosha Bhandarkar

Consultant – Diabetologist
Assistant Professor of Pharmacology
SDMCMS & H, Dharwad
 Drug Metabolism / Bio-transformation

• The chemical modification of drugs in the body

• Render Lipid-soluble(non-polar) compounds

lipid insoluble (polar)

• Enzymes are typically involved in drug metabolism

 Drug Metabolism

Metabolism
More polar Excretion
Drug (water soluble)
Drug

Should not be re-absorbed in the renal tubules and are excreted

Eg. of drugs not requiring Biotransformation (non-polar)

Neostigmine, Gentamicin excreted unchanged in urine
• Biotransformation is the “enzyme catalysed”
chemical alteration of the drug in the body.

Sites of biotransformation : Liver, kidney, intestine, lungs,

placenta & plasma
 Intravenous
Administration

Oral
Administration

Biotransformation Liver

Intestines
 Consequences of biotransformation :

1. “Inactive” metabolite from an “active drug”

2. “Active” metabolite from an “active drug”

3. “Active” metabolite from an “inactive drug” (Prodrug)

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 Consequences of Metabolism
Drug metabolism = Drug Inactivation

• 1. The metabolite may have…

 No or reduced activity (inactivation)
Most drugs and their active metabolite are rendered
inactive.
Examples- Eg. Lignocaine, Paracetamol
Chloramphenicol, Propranolol

Phenobarbitone Hydroxyphenobarbitone
(inactive)
 Consequences Of Metabolism
2. The metabolite may have…
 Equal activity to the drug

“Active” metabolite from an “active drug”

Examples-

Active drug Active metabolite

Diazepam Oxazepam
Codeine Morphine
 Consequences of Metabolism
3. The metabolite of a Prodrug may have…
 Increased activity !

Prodrugs refers to “precursor drug” that in itself has little or

no biological activity, and is metabolised to a
pharmacologically active metabolite.

Features:
– More stable
– Better Bio-availability
– Lesser side effects & toxicity
Some Prodrugs are activated selectively at the site of action
 “Pro”drugs  “Active” drugs

Eg. Levodopa –> Dopamine

Prednisone –> Prednisolone

Becampicillin–> Ampicillin

Imipramine --> Desipramine

 First Pass Effect (First Pass Metabolism)
• Biotransformation of drug by Gut enzymes or Liver
before it reaches systemic circulation
• Results in lower systemic bioavailability of the parent
drug  diminished therapeutic response.
• Requires a higher oral dose for an optimal response
• First pass effect may be bypassed - if the drug is
administered IV or Sublingually

Examples: Isoniazid, Propanolol

 Intravenous
Administration

Oral
Administration

Biotransformation Liver

Intestines
Microsomal Enzymes
 Phases of biotransformation
Phase I reactions Phase II reactions
Non synthetic Synthetic
Reactions with microsomal Reactions with Non-microsomal enzymes
enzymes (mitochondrial or cytoplasmic);
only Microsomal enzyme –
UDP-glucuronidation

oxidation, reduction or Conjugation – acetylation, sulfation etc.

hydrolysis
Metabolites may be active or Metabolites mostly inactive
inactive
 Metabolism Excretion

phase І metabolite
phase ІІ
metabolite

phase ІІ

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1. Phase-I reactions : (Non synthetic)

(i) Oxidation : (most imp)

. Addition of an Oxygen/ Removal of Hydrogen
. Monooxygenase in liver (microsomal)
. Mitochondrial or cytoplasmic enzymes

Eg. : oxidation, hydroxylation,dealkylation and deamination

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• Microsomal oxidation :
. Hydroxylation:
phenobarbitone – p-hydroxy phenobarbital
. Dealkylation :
Amitriptyline – nor triptyline
. Oxidation :
Cimetidine – cimetidine sulfoxide
• Non microsomal oxidation :
. Mitochondrial oxidation : (MAO)
Epinephrine – Vinylmendalic acid
. Cytoplasmic oxidation : ( ALD )
Alcohol – acetaldehyde + acetic acid

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(ii) Reduction : opposite of oxidation
Microsomal (CYP 450 enzymes)
Eg. chloramphenicol, warfarin

(iii) Hydrolysis : cleavage of a drug molecule by taking up of

a molecule of water
Esterases, Amidases, Peptidases
Eg. Choline esters, Lignocaine, polypeptide drugs

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• Cyclization
– Formation of ring structure from a straight chain
compound
– E.g. Proguanil

• Decyclization
– Opening up of ring structure of the cyclic drug
molecule
– E.g. Barbiturates, Phenytoin.
 2. Phase II reactions : (Synthetic/ Conjugation)

. Endogenous substrate (conjugate) gets attached to the

parent drug or the phase I metabolite
(Enzyme – “Transferases”)
 highly ionized organic acid
 becomes inert and more water soluble

. Main route of excretion – urine or bile

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(i) Glucuronide Conjugation : (most imp)
The only Microsomal enzyme in Phase-II reactions
. “UDP- glucuronyl transferase” (UGTs) enzymes
drug + “glucuronide” conjugate

. Not only drugs, but endogenous – bilirubin, steroidal

. Excreted in bile  bacterial flora (gut) “de-conjugation”
. Enterohepatic circulation – prolongs the duration of action
eg. OCPs, Sulfonamides etc.

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Non microsomal conjugation :
(ii) Acetylation : amino or hydrazine residues are
conjugated with acetyl coenzyme-A (acetyl CoA,cytoplasm)
Enzyme – N-acetyl transferase
Eg. Isoniazid, PAS, hydralazine

(iii) Sulfate conjugation : phenolic & steroidal residues

Enzyme – sulfo-transferases
Eg. Adrenal and Ovarian steroids, corticosteroids etc.

(iv) Methyl conjugation : amines & phenols

methionine & cysteine –> methyl donors
Enzyme – transmethylase Eg.Catecholamines, histamine
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(v) Glutathione conjugation :
. Inactivates reactive “quinone/ epoxide” intermediates
. Enzyme : glutathione –S-transferase Eg. Paracetamol
. During poisoining  toxic adducts  tissue damage

(vi) Glycine conjugation :

. Salicylates (carboxylic acid groups) + “glycine”
. Enzyme : glycine transferase . Eg. Aspirin

(vii) Ribonucleoside/nucleotide synthesis:

. Activate many purine & pyrimidine compounds– cancer
chemotherapy drugs
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 Drug metabolizing enzymes :
1. Microsomal enzymes :
Site : smooth ER in the cells of tissues like liver, lungs,
kidney & intestinal mucosa
Principle enzymes : “Cytochrome P-450” (CYP -450)
. Non specific & inducible – drugs, diet, toxins
. Main role in phase I oxidation & reduction reactions

Classification of CYP – 450 :

. Families
. Subfamilies
. Iso-enzymes – Individual genes
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CYP450 Nomenclature
Family

CYP2D6
Sub-Family Individual Gene
Other Microsomal enzymes
• Monooxygenases (Phase I)
• UDP- glucuronyl transferases (Phase –II)

• Role –
Phase I reactions – oxidation, reduction, hydrolysis &
Glucuronide conjugation (Phase –II)
2. Non Microsomal enzymes :

Site : cytoplasm, mitochondria (liver) & plasma

Main role : All phase II reactions (except glucuronidation) &

few phase I reactions

Special features : show inter-individual genetic variations

(polymorphisms) & not inducible.

Eg. Conjugases, Transferase (phase-II)

Oxidase, esterase, amidase (phase-I)

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 3. Non- Enzymatic Metabolism

Hoffmann elimination
- spontaneous Non enzymatic degradation in body
fluids

Eg. Atracurium – plasma

Neonates – low microsomal & glucuronyl
transferase enzyme activity
. Chloramphenicol – ‘Grey baby syndrome’
. Sulfonamides – ‘Kernicterus’
Factors modifying drug metabolism :
Individual Variation In Drug Response
(i) Age :
Neonates – low microsomal & glucuronyl transferase
enzyme activity
. Chloramphenicol – ‘Grey baby syndrome’
. Sulfonamides – ‘Kernicterus’
Elderly - Hepatic blood flow metabolism
Eg. propranolol, lidocaine, pethidine
(ii) Species : eg. Rabbits - Rapidly metabolizes atropine
(iii) Diet : Rich protein & low carbohydrate diet
ses enzyme activity  metabolism of drugs

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 (iv) Genetic polymorphisms : non-microsomal enzymes
• Atypical pseudocholine esterase
succinyl choline Prolonged respiratory arrest -> apnea
• N – acetyl transferase (acetylators) : two types
Slow (Jews, Egyptians) - INH -> Neurotoxicity
Fast (Eskimos,Japanese) - INH -> Hepatotoxicity

(v) Diseases : ex. liver, cardiac, thyroid disorders

(vi) Drug – Drug interactions :

By enzyme inhibition or induction (microsomal enzymes)
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 ENZYME INDUCTION :
. Protective phenomenon against environmental
pollutants
. Prolonged exposure of biological system to
certain chemicals – induction of microsomal
enzymes (CYP - 450) by interacting with DNA

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. Drugs,chemicals & food can induce enzymes –
‘Enzyme inducers’
. Silent features of enzyme inducers :
1. Lipid soluble
2. Different substrate specificities for different
isoenzymes of CYP – 450
Ex. Anticonvulsants – CYP3A4
Cigarette – CYP1A1
3. Long plasma half life (t1/2)
4. Time for induction usually 1-2 wks
5. Reversible process
6. Prominent site - liver (lung, kidney placenta)

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 Pharmacological significance of enzyme induction:
• Drug metabolism accelerated – Efficacy ,
t1/2 and bioavailability of drug
• Pharmacological response of inducer & also
co administered drugs ( metabolizing with
same enzyme)
• formation of active drug or toxic metabolite
– Drug toxicity ( ex.paracetamol)

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Clinical implications of enzyme induction :

• Oral contraceptive pills with rifampicin or

phenytoin – unwanted pregnancy
• Drug tolerance - ex. Carbamazepine, rifampin
• Endogenous substrates – ex. steroids,
bilirubin, sex hormones, Vit.D etc.
• Phenytoin with Vit.D – Osteomalacia
• Barbiturates with oral anti coagulants, oral
hypoglycemics & antiepileptics – Interference
with dose adjustment

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Therapeutic benefits of enzyme induction :
• Phenobarbitone to pregnant mother or to the
infant – prevent jaundice
• Phenytoin – Cushing's syndrome
• Liver diseases

Potent enzyme inducers :

Ex. Phenobarbitone,Carbamazepine,Rifampicin
Phenytoin,Ethanol,Cigarette etc.

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ENZYME INHIBITION :
• Drug metabolism – prolongation or
potentiation of drug effects
• Drug plasma t1/2 , efficacy & toxicity -
• Non specific(microsomal) or specific
enzymes (ex.MAO, xanthine oxidase, ChE )
• Faster ( within hours) & reversible
• Undesirable Drug – Drug interactions
• Prodrugs are not converted to active form

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 Ex.
• Non specific enzyme inhibition :
Cimetidine, erythromycin, chloramphenicol etc.
- Hepatic microsomal enzymes
• Specific enzyme inhibition :
Allopurinol – Xanthine oxidase
Disulfiram – Aldehyde dehydrogenase
Physostigmine – Choline esterase etc.

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Clinical implications of enzyme inhibition :
• Adverse consequences :
Theophylline with chloramphenicol – Nausea
and vomiting
Dicumarol with Cimetidine - bleeding tendency
Terfenadine with chloramphenicol – cardiac
arrhythmias
• Beneficial consequences :
Levodopa with carbidopa – Treat Parkinsonism
Alcohol with disulfiram – Alcohol de addiction

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