BIOTRANSFORMATION OF
DRUGS

Moderator
Dr.B.L Kudagi prof & H.O.D
Introduction
• XENOBIOTICS  Foreign substances to the body.
• Xenobiotic sources – environmental pollution,food
additives...
Biotransformation ( Metabolism )
It is chemical alteration of drugs in the body.
AIM : To convert lipid soluble compounds ...
Significance of biotransformation:
♦ defensive mechanism
♦ increases polarity of drug molecules
 restricts penetration th...
Biotransformation may lead to
1. Bioinactivation : Phenobarbitone to hydroxy
phenobarbitone
2. Bioactivation
a. Activation...
Activation of inactive drug (prodrug)
Prodrug : An inactive form of drug which gets metabolized in the
body to an active d...
Active metabolite from an active drug
•
•
•
•
•
•

Diazepam – Oxazepam.
Amitriptyline – Nortriptyline.
Imipramine – Desimi...
Drug
Paracetamol

Toxic metabolite
N-acetyl -P-

Toxic effect
Hepatoxicity

benzoquinonimine
Isoniazid

Acetylhydrazine

H...
* Hofmann elimination : Atracurium undergoes spontaneous
molecular rearrangement in the plasma
( Non enzymatic Biotransfor...
Patterns of biotransformation
Phases of drug metabolism

Phase I : Nonsynthetic / Functionalization.
Phase II : Synthetic /Conjugation.
Phase I
Enzyme ...
The fate of Phase I(P450) Metabolites
 Inactive
Eg : Many

 Equally active
Eg : Fluoxetine Nor Fluoxetine

 More activ...
Phase I
•

•

•

•
•

Oxidation reactions are carried by
– Cytochrome P450
– Flavin containing monooxygenases.
– Epoxide h...
Phase II
• Enzyme form a conjugate of the substrate
facilitate inactivation of toxic metabolites &
elimination of drugs.
•...
Eg : Phenytoin
Sites of drug metabolism
• Highest level in tissues of GIT (liver ,SI ,LI).
• Liver – major “metabolite clearing house” bo...
Xenobiotic Metabolizing Enzymes
Structure of Cytochrome
• Name – CYP reduced form combine with CO giving a product
whose absorption peak is at 450 nm
• CY...
CYP
• CYP Responsible for metabolizing vast majority of therapeutic drugs.
• Existence of 57 functional genes and 58 Pseud...
Cytochrome P450 3A4/5
• CYP3A4 is responsible for metabolism of 50% of all
drugs
• Expressed in liver,intestine,kidney
• I...
Cytochrome P450 2D6
• This is next most important CYP isoform which
metabolizes nearly 20-30% drugs including
– Antiarrhyt...
Flavin containing Monooxygenases (Ziegler’s enzyme)
• Super family of phase I enzymes expressed at high levels in the live...
Hydrolytic Enzymes
Epoxide Hydrolase

Two Forms: sEH – Expressed in cytosol
mEH – Membrane of ER

Participates in the de...
Conjugation Enzymes
• Phase 2 conjugation enzymes are synthetic in nature – result in
formation of metabolite with increas...
Glucuronidation
• Most important phase 2 reaction catalyzed by UDPGlucuronosyltransferases (UGTs).
• UGT2 – Greater specif...
Sulfation
• SULT located in cytosol metabolise various substrates.
• 11 SULT isoforms identified – role in human homeostas...
N-acetylation
•

Cytosolic N-acetyl transferases (NAT) – most polymorphic of all
human xenobiotic drug metabolizing enzyme...
Methylation
• Xenobiotics undergo O-, N-,S- methylation.
• N-methyltransferase are COMT, POMT, TPMT.
• TPMT – catalysis th...
First pass metabolism (FPM)
Metabolic degradation before the drug reaches
systemic circulation.
Gut lumen : Benzyl Pn. by ...
Drugs with high FPM
a. Oral dose
b. Individual variation
c. In liver disease , Bioavailability
d. 2 drugs competing with ...
Factors affecting (modifying) Drug metabolism.
1. Age.
2. Sex.
3. Species.
4. Nutritional factors.
5. Diseases.
6.Genetic ...
Diseases :Pathological liver condition..
Hypothyroidism  reduces the rate of metabolism.
Hyperthyroidism  enhances the r...
INDUCERS

ENZYMES

drug affected
[increased metabolism]

Phenobarbitone, phenytoin,
Carbamazepaine,
glucocarticoids

CYP3A...
Clinical relavance of enzyme induction
•
•
•
•

OC pills – rifampicin or phenytoin
Warfarin – Barbiturates
Barbiturates – ...
INHIBITORS

ENZYME INHIBITED

Drugs affected
[decreased
metabolism]

Cimetidine

Hepatic microsomal mixed
function oxidase...
Clinical relavence of enzyme inhibition

•
•
•
•
•

• Theophylline - Erythromycin or chloramphenicol
Phenytoin – chloramph...
Role in Drug development process
 Successful drug development - Efficacy & Safety.
 Compound subjected to analysis by hu...
References
• Pharmacological basis of Therapeutics – Goodman & Gilman
12th Edition .
• Principles of pharmacology – HL Sha...
Thank u
Biotransfermation of drugs by harsha
Biotransfermation of drugs by harsha
Biotransfermation of drugs by harsha
Biotransfermation of drugs by harsha
Biotransfermation of drugs by harsha
Biotransfermation of drugs by harsha
Biotransfermation of drugs by harsha
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Biotransfermation of drugs by harsha

  1. 1. BIOTRANSFORMATION OF DRUGS Moderator Dr.B.L Kudagi prof & H.O.D
  2. 2. Introduction • XENOBIOTICS  Foreign substances to the body. • Xenobiotic sources – environmental pollution,food additives,agrochemicals,drugs , others • Large no.of diverse enzymes metabolize xenobiotics been called xenobiotic metabolizing enzymes. • Lipophilic chemicals in absence of metabolism would not be efficiently eliminated , resulting in toxicity. • Metabolism convert these hydrophobic chemicals into hydrophilic derivatives that can be easily eliminated – diminishing biological activity.
  3. 3. Biotransformation ( Metabolism ) It is chemical alteration of drugs in the body. AIM : To convert lipid soluble compounds to lipid insoluble so that they are not reabsorbed . Site : Liver, GIT, Lungs, kidney, plasma, skin,others
  4. 4. Significance of biotransformation: ♦ defensive mechanism ♦ increases polarity of drug molecules  restricts penetration through cellular membrane  reduces distribution  promotes elimination
  5. 5. Biotransformation may lead to 1. Bioinactivation : Phenobarbitone to hydroxy phenobarbitone 2. Bioactivation a. Activation of inactive drug ( prodrug ) b. Active metabolite from an active drug c. Toxic metabolites from relatively non-toxic drugs.
  6. 6. Activation of inactive drug (prodrug) Prodrug : An inactive form of drug which gets metabolized in the body to an active drug. Eg : 1. Levodopa – Dopamaine. 2. Enalapril – Enalaprilat. 3. Valacyclovir – Acyclovir 4. Sulfasalazine – Mesalazine(5-ASA)
  7. 7. Active metabolite from an active drug • • • • • • Diazepam – Oxazepam. Amitriptyline – Nortriptyline. Imipramine – Desimipramine. Codeine – Morphine Digitoxin – Digoxin Procainamide – N-acetyl procainamide
  8. 8. Drug Paracetamol Toxic metabolite N-acetyl -P- Toxic effect Hepatoxicity benzoquinonimine Isoniazid Acetylhydrazine Hepatoxicity Halothane Alkylating metabolites Hepatoxicity Cyclophosphamide Acrolein Sodium nitroprusside Thiocyanate Haemoohagic cytitis Acute toxic psychosis
  9. 9. * Hofmann elimination : Atracurium undergoes spontaneous molecular rearrangement in the plasma ( Non enzymatic Biotransformation ) * Most hydrophilic drugs are little biotransformed and are largely excreted unchanged Ex: streptomycin , neostigmine
  10. 10. Patterns of biotransformation
  11. 11. Phases of drug metabolism Phase I : Nonsynthetic / Functionalization. Phase II : Synthetic /Conjugation. Phase I Enzyme carry out Oxidation, Reduction ,Hydrolytic reactions. Introduction of functional groups resulting in a modification of the drug. To increase the water solubility of the drug usually leads to inactivation of the active drug.
  12. 12. The fate of Phase I(P450) Metabolites  Inactive Eg : Many  Equally active Eg : Fluoxetine Nor Fluoxetine  More active Eg : Losartan Active Metabolite (E -3174)  Toxic Eg : Acetominophen  N acetyl- p – benzoquinoneimine (NABQI)  Activation of ‘prodrug’ Eg : levo dopa  Dopamine.
  13. 13. Phase I • • • • • Oxidation reactions are carried by – Cytochrome P450 – Flavin containing monooxygenases. – Epoxide hydrolases (EH) Reduction reaction -NADPH cytochrome – C – reductase -Nitro reductase. -Azo reductase. -Keto reductase Hydrolysis reaction -Epoxide hydrolase -carboxylesterases Cyclization. Decyclization. • Enzyme either adds or exposes a functional group – serve as substrates for the phase II
  14. 14. Phase II • Enzyme form a conjugate of the substrate facilitate inactivation of toxic metabolites & elimination of drugs. • Produce metabolite with improved water solubility & increased molecular weight. • Several conjugating enzymes are glutathione S transferase (GST),UGT,SULT,NAT,MT. • Require substrate to have O2 , N2 ,S atoms that serve as acceptor site.
  15. 15. Eg : Phenytoin
  16. 16. Sites of drug metabolism • Highest level in tissues of GIT (liver ,SI ,LI). • Liver – major “metabolite clearing house” both for endogenous chemicals & xenobiotics. • Xenobiotic metabolising enzymes located in epithelial cells of GIT – initial metabolic processing of most oral medication.(1st pass metabolism) • Drug poorly metabolized remain longer period of time & has longer elimination half lives. • Other organs : tissues of nasal mucosa , lung , blood , CNS, kidney.
  17. 17. Xenobiotic Metabolizing Enzymes
  18. 18. Structure of Cytochrome • Name – CYP reduced form combine with CO giving a product whose absorption peak is at 450 nm • CYP are superfamily of enzymes containing molecule of heme that is non covalently bound to polypeptide chain. • CYP uses O2, CYP 450, CYP450 reductase, NADPH for oxidation of substrates.
  19. 19. CYP • CYP Responsible for metabolizing vast majority of therapeutic drugs. • Existence of 57 functional genes and 58 Pseudo genes in humans. • Genes grouped based on AA sequence into a large number of families and sub families. • Cytochrome P450 Nomenclature, e.g. for CYP2D6 » CYP = cytochrome P450 » 2 = genetic family » D = genetic sub-family » 6 = specific gene • In Humans 12 CYP’s involved in xenobiotic metabolism fall into families 1 -3.
  20. 20. Cytochrome P450 3A4/5 • CYP3A4 is responsible for metabolism of 50% of all drugs • Expressed in liver,intestine,kidney • Inducers Barbiturates,Carbamazepaine,phenytoin,rifampicin • Inhibitors -Erythromcin,clarithromycin,ketoconazole,flucanazole
  21. 21. Cytochrome P450 2D6 • This is next most important CYP isoform which metabolizes nearly 20-30% drugs including – Antiarrhythmics, β- blockers – Trcyclic antidepressant,SSRIs • Inhibition of the enzyme by quinidine results in failure of conversion of codine to morphine, analgesic effect of codeine is lost.
  22. 22. Flavin containing Monooxygenases (Ziegler’s enzyme) • Super family of phase I enzymes expressed at high levels in the liver bound to ER. • Six families of FMOs, FMO3 – most abundant in the liver. • Metabolize nicotine, H2 receptor blocker, antipsychotics [clozapine], antiemetics [itopride]. • Genetic deficiency  Fish odor syndrome due to lack of metabolism of TMAO [ trimethylamine N oxide ]  TMA. • Minor contributors to drug metabolism - produce benign metobolites. • Not involved in drug-drug interactions. • Eg : Itopride metabolized by FMO3 : Cisapride metabolized by CYP3A4
  23. 23. Hydrolytic Enzymes Epoxide Hydrolase  Two Forms: sEH – Expressed in cytosol mEH – Membrane of ER  Participates in the deactivation of potentially toxic derivates generated by CYP eg: Carbamazepine to carbamazepaine 10 and 11 epoxide by a CYP. * valproic acid inhibit mEH- significant DI with Carbamazepine. This leads to efforts to devolp new drugs such as gabapentin that is metabolized by CYPs and not by EHs *
  24. 24. Conjugation Enzymes • Phase 2 conjugation enzymes are synthetic in nature – result in formation of metabolite with increase in molecular mass. • Terminate biological activity of the drug. • Characteristic feature – dependency on the catalytic reaction for cofactors such as UDP-GT,PAPS,GST,NAT,SULT. • All reactions are carried out in cytosol of the cell, exception of glucuronidation. • Catalytic rates of phase 2 reaction are significantly faster than rates of CYP’s. • So rate of elimination depends on Phase 1.
  25. 25. Glucuronidation • Most important phase 2 reaction catalyzed by UDPGlucuronosyltransferases (UGTs). • UGT2 – Greater specificity for glucuronidation of steroids. • UGT1A1 – Glucuronidation of bilirubin. Crigler Najjars syndrome type 1 & type 2 • Most common genetic polymorphism – Gilberts syndrome (10%) (mutation in UGT1A1 gene). • Drug toxic are simvastatin,atorvastatin,ibuprofen,ketoprofen
  26. 26. Sulfation • SULT located in cytosol metabolise various substrates. • 11 SULT isoforms identified – role in human homeostasis. SULT1B1  catalysis of cholesterol . SULT1A3  catecholamine SULT1E1  estrogens SULT2A1  DHEA SULT1 Sulfation of phenolic molecules. • SULT1A1  Most abundant in human tissue.
  27. 27. N-acetylation • Cytosolic N-acetyl transferases (NAT) – most polymorphic of all human xenobiotic drug metabolizing enzymes. Eg: Isoniazid – (5-15%), experience toxicities. • Two functional NAT gene in human, slow acetylation pattern attributed mostly to polymorphism in NAT 2 gene. Slow phenotype predisposed to toxicity Hydralazine (NAT2) at therapeutic doses  extreme hypotension and tachycardia in slow acetylators. Sulfonamides  slow acetylators are predisposed to drug induced hypersensitivity reactions. • • •
  28. 28. Methylation • Xenobiotics undergo O-, N-,S- methylation. • N-methyltransferase are COMT, POMT, TPMT. • TPMT – catalysis the S- methylation of aromatic and cyclic sulfhydryl compounds. • Genetic deficiency of TPMT – severe toxicities of thio purine drugs.(Azathioprine , 6-mercaptopurine )
  29. 29. First pass metabolism (FPM) Metabolic degradation before the drug reaches systemic circulation. Gut lumen : Benzyl Pn. by acid , Insulin by proteolytic enzyme Liver : Main site of metabolism Skin : Transdermally administered drugs Lungs : Drugs reaching venous blood through any route.
  30. 30. Drugs with high FPM a. Oral dose b. Individual variation c. In liver disease , Bioavailability d. 2 drugs competing with each other’s FPM. Ex :- CPZ & propranolol
  31. 31. Factors affecting (modifying) Drug metabolism. 1. Age. 2. Sex. 3. Species. 4. Nutritional factors. 5. Diseases. 6.Genetic variation 7.Drug-Drug interaction
  32. 32. Diseases :Pathological liver condition.. Hypothyroidism  reduces the rate of metabolism. Hyperthyroidism  enhances the rate of metabolism. Genetic factors :•Genetic variation in the rate of drug metabolism  Fast / slow acetylators. Eg : Isoniazid.  Atypical pseudocholinesterase. Eg : Succinylcholine.  Faulty expression of CYP2D6 Eg: codeine
  33. 33. INDUCERS ENZYMES drug affected [increased metabolism] Phenobarbitone, phenytoin, Carbamazepaine, glucocarticoids CYP3A4 Rifampicin, phenobarbitone CYP3A4&2C9 Oral Contraceptives, Warfarin Smoking, omeprazole CYP1A2 Warfarin,Theophylline Chronic ethanol intake, Isoniazed CYP2E1 Ethanol itself ,General anaesthetics Barbiturates,CCB, Theophylline
  34. 34. Clinical relavance of enzyme induction • • • • OC pills – rifampicin or phenytoin Warfarin – Barbiturates Barbiturates – own metabolism Ethanol drinkers – paracetamol ( N acetyl p benzoquinoneimine ) • Neonatal jaundice – Phenobarbitone • Cushings syndrome - phenytoin
  35. 35. INHIBITORS ENZYME INHIBITED Drugs affected [decreased metabolism] Cimetidine Hepatic microsomal mixed function oxidase Phenytoin, Warfarin, Anti Depressants, Theophyline, Diazepam, Quinidine, Testosterone Sodium valpaorate Hepatic microsomal mixed function oxidase Phenytoin, phenobarbital, primidon Erythromycin Hepatic microsomal mixed function oxidase Theophyline, Warfarin, carbamazepine, cyclosporin Disulfiran,tolbutamide, metranidazole Aldehyde dehydrogenase Alcohol,Warfarin Carbidopa L-aromatic aminoacid decorboxylase L-dopa
  36. 36. Clinical relavence of enzyme inhibition • • • • • • Theophylline - Erythromycin or chloramphenicol Phenytoin – chloramphenicol or dicumarol Terfenadine – Ketaconazole or Chloramphenicol L-dopa – Carbidopa Alcohol – disulfiran or Metranidazole d-tubocurarine - Neostigmine
  37. 37. Role in Drug development process  Successful drug development - Efficacy & Safety.  Compound subjected to analysis by human liver cells or extracts , to predict the rate of metabolism.  If a single CYP metabolizes , then decision can be made about drug interaction especially for elderly people.  Ideal drug candidate – metabolized by several CYP’s so that variability in expression levels of one CYP not significantly impact its metabolism and Pk
  38. 38. References • Pharmacological basis of Therapeutics – Goodman & Gilman 12th Edition . • Principles of pharmacology – HL Sharma & KK sharma 2nd edition . • Pharmacology – Rang & Dale 6th Edition. • Text book of pharmacology – K. D. Tripathi.7th Edition. • Basics & clinical pharmacology – Katzung 11th edition
  39. 39. Thank u
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