This document discusses biotransformation, or the metabolic processes by which living organisms transform xenobiotics like drugs. It covers the phases of drug metabolism including phase I reactions like oxidation and reduction and phase II reactions like glucuronidation and sulfation. Key enzymes involved in biotransformation are cytochrome P450 enzymes and UDP-glucuronosyltransferases. The document also discusses factors that can influence drug metabolism like age, sex, nutrition, disease states, genetic variations and drug-drug interactions.

1. BIOTRANSFORMATION
Dr CHINTAN DOSHI
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2. Topics to be discussed
Introduction to Biotransformation
The Phases of Drug Metabolism
Enzyme Induction & Inhibition
Enzymes Metabolising Xenobiotics
Sites of Drug Metabolism
Factors affecting Drug metabolism
( Biotransformation )
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3. Coping with Exposure to Xenobiotics
• Humans come into Contact with foreign chemicals, medicines, or
Xenobiotics (substances foreign to body) Through –
- Intentional exposure,
- Accidental exposure,
- Diet.
• Fortunately, a mechanism to rapidly eliminate them is developed
⇓
• They do not accumulate in & harm the body
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4. BIOTRANSFORMATION
• Definition :-
“ Biochemical Transformation of
Drugs within the Living Organism,
catalyzed by Enzymes. ”
• Aim :-
 Water insoluble → water soluble → easily
excreted
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5. • Advantage :
 Critical for survival
• Disadvantage :
 Inter-individual variations
 Drug-Drug interactions
 Toxic & Carcinogenic derivatives
 Species differences → limits the use of animal models in new drug
development
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6. Consequences of Biotransformation
 Active Drug ⇒ Inactive Metabolite :
Phenobarbitone → Hydroxyphenobarbitone
( Active Drug ) ( Inactive Metabolite )
 Inactive Drug ( Prodrug ) ⇒ Active Metabolite :
L-Dopa → Dopamine
( Prodrug ) ( Active )
 Active Drug ⇒ Equally Active Metabolite
Diazepam → Oxazepam
( Active ) ( Active )
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7. Active drug Active metabolite
Chloral hydrate Trichloroethanol
Digitoxin Digoxin
Imipramine Desipramine
Amitriptyline Nortriptyline
Codeine Morphine
Losartan E 3174
7

8. Prodrug
Prodrug Active form
Levodopa Dopamine
Enalapril Enalaprilat
a-Methyldopa a-methylnorepinephrine
Dipivefrine Epinephrine
Bacampicillin Ampicillin
Acyclovir Acyclovir triphosphate
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9. First-Pass Metabolism
• Drug ⇒ Oral administration ⇒ G.I.T. ⇒ Portal circulation ⇒
Liver ( First pass metabolism ) ⇒ Systemic Circulation
• Decreases Bioavailability
• Decreases Therapeutic Response
• Can be bypassed if drug is given –
- Parenterally ( i.v. Xylocaine in Arrhythmias )
Or
- Sublingually ( Isosorbide dinitrate in Angina )
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10. Drugs Undergoing First-pass Metabolism
10
Liver Intestine
Bronchial Mucosa
• Morphine
• Xylocaine
• Imipramine
• Propranolol
• GTN
• L- Dopa
• Testosterone
• Progesterone
• Chlorpromazine
• Nicotine
• Isoprenaline

11. Site Of
Biotransformation
In Cell
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12. Chemical Pathways Of
Drug Metabolism
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13. THE DRUG METABOLIZING ENZYMES
(1) Microsomal Enzymes :
• Location : - Smooth Endoplasmic Reticulum of Liver cells,
- Intestinal mucosa, Lungs, Kidney.
• Activity : - Phase 1 reactions
- Phase 2 reaction ( Glucuronyl conjugations )
• Example : - Cytochrome P-450 enzymes
• Metabolize only Lipid-soluble drugs

14. (2) Non-Microsomal Enzymes :
• Location : - Cytoplasm,
- Mitochondria of Hepatic cells,
- Plasma.
• Activity : - All Phase 2 reactions ( Except Glucuronyl conjugation )
• Example : - Esterase, - Monoamine Oxidase (MAO),
- Amidase, - Transferase.
(3) Non-enzymatic ( Hofmann ) Elimination :
• Spontaneous Molecular rearrangement, without any enzyme action
• Example - Atracurium
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15. Phases of Drug Metabolism
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Phase 1 Phase 2
• Introduction of functional
groups. -OH, -COOH, -SH ,-NH2
• Alters biological property
• Oxidation/Reduction Reactions
• Enzymes - CYPs, FMO
• Slower reaction rate
• Conjugation of substrate
• Alters Solubility and mol. wt.
• Conjugation / Hydrolysis
• Enzymes - Transferases, EH
• Faster reaction rate

16. PHASE-1 REACTION
ENZYMES
 CYP ( Cytochrome-P450 )
 FMO ( Flavin-containing Monooxigenases )
 Hydrolytic enzymes
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17. Cytochrome P-450
• Location :- Endoplasmic Reticulum
• Structure :-
Heme ⇿ Polypeptide chain
• Nomenclature :
- CYP → Digit for Family → Letter for Subfamily → Gene number
- e.g. – CYP3A4 ⇒ - Cytochrome P-450
- Family “ 3 ”
- Subfamily “ A ”
- Gene Number “ 4 ”
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18. 04-Jan-14 18

19. PHASE-1 REACTIONS
 Oxidation
 Reduction
 Hydrolysis
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20. CYP-dependent Oxydation Reactions
(1) Aromatic Hydroxylation:
 Phenytoin
 Warfarin
 Ethinyl estradiol
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21. (2) Alliphatic Hydroxylation :
 Ibuprofen
 Phenobarbital
 Cyclosporin
 Midazolam
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22. 04-Jan-14 22
• Deamination
• Amphetamine
• Diazepam
Carbinolamine
intermediate
• Dehalogenation
• Halothane
Hepatotoxicity

23. 04-Jan-14 23
• N-Oxidation
• Dapsone
• S-Oxidation
• Chlorpromazine

24. Reduction
•CYP-450 work in opposite direction
• Alcohol, Aldehyde
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25. Hydrolysis
•Ester + H20 Acid+alcohol
•Choline ester
•Lignocaine
•Procaine
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26. cyclization
•Formation of ring structure
•Ex.: proguanil
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27. Decyclization
•Opening of ring structure
•Barbiturate, phenytoin
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28. PHASE -2 REACTIONS
 Glucuronidation
 Sulfation
 Glutathione conjugation
 N-acetylation
 Methylation
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29. Glucuronidation
• Enzyme : UGT ( UDP-glucuronosyltransferases )
• Co-factor- UDP-glucuronic acid
• Location : - Liver,
- G.I. epithelial cells
• UGT-1 is more important than UGT-2 in drug metabolism
• drugs metabolized : - Morphine,
- Erythromycin
- Paracetamol
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30. Sulfation
• Enzyme : - Sulfotransferase
• Co-factor : - Phosphoadenosyl phosphosulfate
• Drugs : - Methyl dopa
- Ethinyl estradiol
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31. Glutathione Conjugation
• Co-factor : - Glutathione(GSH)
• Enzyme : - GST
(Glutathione-S-Transferase)
•Serves to inactivate highly reactive
quinone or epoxide intermediates formed during
metabolism of certain drugs, e.g. paracetamol
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32. N-Acetylation
• Co-factor : - Acetyl CoA
• Enzyme : - N-Acetyl Transferase ( NAT )
• Drugs : - Amide-containing drugs,
e.g. – Isoniazid
- Sulfonamide
- Dapsone
- Clonazepam
- Para aminosalicylic acid
Procainamide
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33. Methylation
• Cofactor : - S-Adenosylmethionine [ SAM ]
• Enzyme : - Methyltransferase ( MT ) (cytosol)
• Highly substrate specific
• Drugs :
- TPMT--- Azathioprine, 6-MT, thioguanine
- COMT --- dopamine, methyl dopa, nor- epinephrine
- HNMT --- Histamine
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34. Ribonucleoside/nucleotide synthesis
•This pathway is important for the activation of
many purine and pyrimidine antimetabolites
•Used in cancer chemotherapy.
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35. INDUCTION OF
DRUG METABOLISM
35

36. Clinical relevance
(A) Decreased Plasma Concentration & Therapeutic effect :
36
Enzyme inducer
• Phenobarbitone
• Phenytoin
• Carbamazepine
• Rifampicin
• Smoking
• Ethanol (chronic)
• Isoniazid

37. (B) Drug Toxicity :
Ethanol drinkers
⇓
Paracetamol
⇓
N-acetyl-P-benzoquinoneimine
⇓
Hepatotoxicity
37

38. (C) Therapeutic benefits :
Phenobarbitone given 7 – 14 days before labour
⇓
Induces foetal hepatic glucuronyl transferase enzyme
⇓
Conjugation of bilirubin to glucuronic acid
⇓
Excreted through bile
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39. • Enzyme inducer like phenytoin increase metabolism ofVitamin D & leads
osteomalacia
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40. ENZYME INHIBITION
40

41. Clinical consequences
(A) Increased plasma concentrations & toxicity :
41
Inhibitor Enzyme inhibited Drugs affected
• Cimetidine
• Hepatic microsomal
MFO
(Mixed Function Oxidase)
• Phenytoin
• Warfarin
• Theophylline
• Allopurinol • Xanthine oxidase • Azathioprine
• MAO inhibitors • Monoamine oxidase
• Morphine
• Tricyclic
antidepressants

42. (B) Therapeutic benefits :
 L- dopa + carbidopa
 Disulfiram + Alcohol ⇒ Alcohol aversion therapy
42

43. Factors affecting drug metabolism
 Age :
 Neonates :
• Low activity of glucuronyl transferase enzyme
⇓
Choramphenicol
⇓
“ Gary baby syndrome ”
 Elderly :
 Decreased hepatic blood flow
 ⇓
 Propranolol, Pethidine toxicity
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44. Contd.
 Sex :Male rate sleep short duration than female after hexobarbitione as
microsomal enzyme activity is higher
 Nutrition & diet: rich in protein & low in carbohydrate ↑rate
 Disease:
Hypothyrodism ↓ metabolism of methimazole & digoxin
Hyperthyrodism ↑ metabolism of various drugs
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45. Contd.
Species:
Rabbit metabolite atropine faster than male
Race
Chinese have low aldehyde dehydrogenase activity
Exhibit higher concentration of aldehyde after consuming alcohol
Genetic variation
Slow acetalators :higher chance of peripheral neuropathy with isoniazid
Atypical psuedocholineesterase: prolong dyspnoea by succinylcholene
Drug-drug interactions
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