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Biotransformation.pptx

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Arun Kumar

This document discusses biotransformation, or the metabolism of drugs in the body. It covers the key topics of: - Phases of metabolism, including phase 1 reactions like oxidation and reduction mediated by cytochrome P450 enzymes, and phase 2 conjugation reactions. - Important cytochrome P450 enzyme families, specifically CYP3A4 which metabolizes over 50% of drugs. - Factors that can influence biotransformation like concurrent drug use, genetic polymorphisms, and pathological states. - The role of biotransformation in drug discovery and development through in vitro and in silico studies.

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BIOTRANSFORMATION (Metabolism of drugs) Dr. Arun kumar. R PGY1 Department of Pharmacology SRM MCH & RC
OUTLINE ➢ Introduction ➢ Phases of metabolism ➢ Phase 1 metabolism ➢ Cytochrome P family ➢ Phase 2 metabolism ➢ First pass metabolism ➢ Microsomal drug induction ➢ Drug inhibition ➢ Factors affecting biotransformation ➢ Biotransformation in drug development ➢ Take home message
Clinical vignette Q. A 68 year old woman is brought to the emergency for treatment of chest pain. She is currently taking aspirin and clopidogrel daily, as well as omeprazole for heartburn. What can be the most likely contributor to her symptoms?
Biotransformation Chemical alteration of drug in the body that converts non polar or lipid soluble compounds to polar or lipid insoluble compounds Why does metabolism occur ? The many therapeutic agents that are lipophilic, hydrophobic do not pass readily into the aqueous environment of the urine, in the absence of metabolism, they accumulate in fat and cellular phospholipid bilayers Xenobiotics - substances foreign to the body, can be from natural or artificial sources.
The metabolism of drugs and other xenobiotics into more hydrophilic metabolites is essential for termination of their biological, pharmacological activity and can easily be eliminated from the body through the urine or the bile Consequences: • Inactivation - Formation of an inactive metabolite from an active drug, that is readily excreted from the body (Ex: Phenobarbitone Hydroxyphenobarbitone) • Active metabolite from an active drug (Ex: Diazepam Oxazepam) • Activation of inactive drug (Generate biologically active metabolites, Ex: Levodopa) • Toxic to non toxic metabolite
Sites : Liver, GI tract, Kidneys, Lungs, Plasma Liver: Major site (Eg: Morphine, Prazosin, Paracetamol, Lidocaine, Nitroglycerine) GIT: Insulin, Catecholamines, Salbutamol, Clonazepam, Chlorpromazine Lung: Prostanoids Plasma: Succinylcholine, Adenosine Placenta: Alcohol
1. Phase 1 reactions/ Non-synthetic [oxidation/ reduction/ hydrolysis, CYPs] Introduction of functional groups such as (–OH, –COOH, –O–, or NH2) and converts parent drug to more polar metabolite. 1. Phase 2 reactions/ Synthetic [conjugation] Conjugation reactions in which a covalent linkage is formed between a functional group on the parent compound or phase 1 metabolite and an endogenous substrate like glucuronic acid, sulfate, acetate or an amino acid. Biotransformation reactions
Q. Which of the following reactions represents Phase II of drug metabolism ? a) Amidation b) Hydrolysis c) Oxidation d) Reduction e) Sulfation
Phase 1 reactions/ Non-synthetic Phase 2 reactions/ Synthetic Biotransformation ● Oxidation ● Reduction ● Hydrolysis ● Cyclization ● Decyclization ● Glucuronide conjugation ● Acetylation ● Methylation ● Sulphate conjugation ● Glycine conjugation ● Glutathione conjugation ● Ribonucleoside or nucleotide synthesis
Phase I Phase II oxidation/ reduction/ hydrolysis Drugs directly enter Phase II metabolism Conjugation drug is usually inactive After Phase I the drug may be activated, inactivated or unchanged DRUG/ XENOBIOTICS Conjugation products
Biotransformation reactions Bertram G. Katzung , Todd W. Vanderah ,Basic & Clinical Pharmacology 15th Edition
Metabolising enzymes Goodman & Gilman's the pharmacological basis of therapeutics
Drug metabolising enzymes : Microsomal enzymes Site: These enzymes are present in the smooth endoplasmic reticulum of the liver, lungs, kidney and intestinal mucosa. Principal enzymes: Cytochrome P - 450 MFOs (mixed function oxidases) Microsomal enzymes are concerned with Phase 1 reactions - oxidation, reduction, hydrolysis and glucuronyl conjugation of Phase 2
Goodman & Gilman's the pharmacological basis of therapeutics
Phase 1 or Non synthetic reactions Oxidation: Addition of oxygen (negatively charged radical) or removal of hydrogen (positively charged radical) Reactions are carried out by a group of monooxygenases in the liver Important oxidation reactions are hydroxylation, oxygenation at C, N or S atoms, oxidative deamination etc., Microsomal oxidations - those catalysed by microsomal enzymes (CYP dependent)
Multiple CYP gene families have been identified in humans and categorized based on protein sequence homology The cytochrome P-450 isoenzymes are identified and grouped into more than 20. Families - 1,2,3…. (CYP1) Most of the drug metabolising enzymes are in CYP 1,2 & 3 families. Subfamilies are identified as A, B & C… (CYP1A) An additional numeral when isoform is identified (CYP1A2) Italics indicate gene (CYP1A2); regular font is enzyme(CYP1A2) Isoenzyme families important in humans are CYP1, CYP2, CYP3 Cytochrome P family
Cytochrome enzymes Goodman & Gilman's the pharmacological basis of therapeutics
Carryout biotransformation of largest number (30- 50%) of drugs. In addition to liver, these isoforms are expressed in intestine (responsible for first pass metabolism at this site) and kidney as well. Example: Inhibition of CYP3A4 by erythromycin, ketoconazole etc., Rifampicin, phenytoin, carbamazepine are inducers of CYP3A4 CYP3A4/5
Cytochromes : Metabolism of drugs Tripathi, K. D. (2018). Essentials of medical pharmacology (8th edition)
Tripathi, K. D. (2018). Essentials of medical pharmacology (8th edition)
Monoamine oxidase (MAO), Diamine oxidase (DAO) MAO (mitochondrial) oxidatively deaminates endogenous substrates including neurotransmitters. Dopamine, Serotonin, norepinephrine, epinephrine Alcohol & Aldehyde dehydrogenase Non-specific enzymes found in soluble fraction of liver Ethanol metabolism Flavin monooxygenases These enzymes are involved in metabolism of drugs like ranitidine Non CYP drug oxidations:
This reaction is the converse of oxidation and involves cytochrome P-450 enzymes working in the opposite direction. Alcohols, aldehydes, quinones are reduced. Drugs primarily reduced are chloralhydrate, chloramphenicol, halothane, warfarin Reduction process catalysed by microsomal enzymes Reduction
Site: Hydrolysis occurs in liver, intestines, plasma and other tissues. Microsomal hydrolysis: Hydrolytic reactions are rarely microsomal, except for Example: 1. Pethidine to Pethidinie acid (meperidinie) 2. Lidocaine hydrolysis Non -microsomal hydrolysis: Enzymes involved are esterases, amidases. Example: 1.Procaine to PABA by plasma choline esterases 2.Atropine to tropic acid 3.Hydrolysis of penicillin-G & procainamide by amidases Hydrolysis
Cyclization Formation of a ring structure from a straight chain compound Ex: Proguanil Decyclization Opening up of ring structure of the cyclic drug molecule Ex: Barbiturates, Phenytoin Cyclization and Decyclization
Conjugation of the drug or its phase I metabolite with an endogenous substrate To form a polar, highly ionized organic acid, which is easily excreted in urine or bile Conjugation reactions have high energy requirement and are generally faster than phase 1 reactions Phase 2 reactions/ Synthetic [conjugation]
• Carried out by a group of UDP-glucuronosyl transferases (UGTs) • Compounds with a phenolic, alcoholic, hydroxyl or carboxylic acid group are easily conjugated with glucuronic acid Example: • Chloramphenicol, aspirin, paracetamol, diazepam, lorazepam, morphine • Other than drugs, endogenous substrates like bilirubin, steroidal hormones and thyroxine utilize this and gets excreted in the bile Drug glucuronides excreted in bile can be hydrolysed by bacteria in the gut- the liberated drug is reabsorbed and undergoes the same fate. This enterohepatic cycling of the drug prolongs its action. Example: oral contraceptives. Glucuronide conjugation: [Microsomal conjugation]
Non –microsomal conjugation N-Acetyl conjugation Site: Cytoplasm Catalysed by N-Acetyl transferase using acetyl coenzyme-A Important in sulfonamide metabolism because acetyl-sulfonamides are less soluble than the parent compound and may cause renal toxicity due to precipitation in kidney. Example : Isoniazid, Dapsone, Sulfonamides, Histamine
Sulfate conjugation Site: Cytoplasm Major pathway for phenols, also occurs for alcohol, amines Catalysed by Sulfotransferases using PAPS (3-phosphoadenosine-5-phosphosulfate) Infants and young children have predominating O-sulfate conjugation Example : Aspirin, Paracetamol, Corticosteroids, Methyldopa, Chloramphenicol
Non–microsomal conjugation : Minor metabolic pathways Amino acid conjugation: Site: mitochondria • ATP dependent acid: CoA ligase forms CoA-amino acid conjugates which then react with drugs by N-Acetylation • Drugs like Nicotinic acid, Aspirin, Benzoic acid, Glycine, Arginine Methyl conjugation: Site: cytoplasm • Drugs like Dopamine, Epinephrine, Histamine are catalysed by enzyme transmethylase with S-adenosine methionine
Minor metabolic pathways - contd.. Glutathione conjugation: Glutathione is a protective factor for removal of potentially toxic compounds Site: cytoplasm Drugs like ethacrynic acid, sulfobromophthalein, Paracetamol are catalysed by enzyme g- glutamyl transpeptidase - the products can be further acetylated to N-acetylcysteine conjugate. Example: Paracetamol Ribosides and Riboside Phosphates: Purines & pyrimidines, used as antimetabolites in chemotherapy, form their active metabolites by forming ribonucleosides and ribonucleotides.
Phase II reactions • Some drugs are directly metabolised by phase II reactions, before phase I • Same drugs can be metabolised by different enzymes simultaneously Ex: Amitriptyline metabolised by CYP2D6, CYP2C9, CYP2C19 • Same CYP can metabolise different drugs simultaneously Ex: CYP3A4 can bind metabolize diazepam and testosterone simultaneously Isoniazid Hydrolysis (phase I) N-acetyl conjugate (phase II)
Spontaneously metabolised in plasma through molecular rearrangement No enzyme action involved Example: Atracurium (skeletal muscle relaxant) Non-enzymatic Biotransformation HOFMANN ELIMINATION
First Pass Metabolism/ Pre - systemic elimination/ First pass effect Metabolism of a drug during its passage from the site of absorption into the systemic circulation. Occurs for drugs that are taken orally. • Significant amount of drug is inactivated before reaching systemic circulation • Certain amount of drug is absorbed as it passes through GIT wall and portal circulation. • Decreased bioavailability of the drug • Diminished therapeutic effect • Bypassed by parenteral administration of drug - intravenous and sublingual.
Attributes of drugs with high first pass metabolism • Oral dose is considerably higher than sublingual or parenteral dose • Marked individual variation in the oral dose due to differences in the extent of first pass metabolism • Oral bioavailability of a drug is increased if another drug is competing with it • Oral bioavailability is apparently increased in patients with severe liver disease Example: Propranolol Principles of Pharmacology by H. L. Sharma and K. K. Sharma
Microsomal enzyme induction • A number of drugs, many carcinogenic chemicals and insecticides on repeated administration increase the synthesis of microsomal enzyme protein i.e increase the rate of metabolism. • As this requires synthesis of proteins, induction takes 4 - 14 days to reach its peak and equal time to dissipate after the enzyme inducer is stopped.
Different inducers are selective for certain forms of cytochrome P-450 enzyme CYP3A is induced by - Antiepileptic drugs : Phenobarbitone, Rifampicin and Glucocorticoids. CYP2E1 is induced by - Isoniazid, Chronic alcohol consumption CYP1A is induced by - Cigarette smoking, Industrial pollutants, Charcoal broiled meat
ENZYME INDUCTION Principles of Pharmacology by H. L. Sharma and K. K. Sharma
Clinical relevance of enzyme induction Decreased intensity of therapeutic effect of the drug. Example: Failure of Oral contraceptive pills, Warfarin if enzyme inducers like phenytoin or rifampicin are used concomitantly. Smoking (polycyclic aromatic hydrocarbons) and theophylline. Increased intensity of therapeutic effect of the drug. Example: Hepatotoxicity from paracetamol in alcoholics
Tolerance - autoinduction Example: Barbiturates, Carbamazepine enhance their own metabolism leading to tolerance. Interfere with adjustment of dose of another drug and side effects like osteomalacia. Therapeutic benefits: The knowledge of enzyme induction can also be used for therapeutic benefits Example: To treat neonatal jaundice - Phenobarbitone
Inhibition of metabolism One drug may competitively inhibit the metabolism of another drug - if it utilizes same enzyme Unlike induction it is a rapid process and usually reversible A drug may inhibit one isoenzyme while being itself a substrate for another isoenzyme. Example: Quinidine - metabolised by CYP3A4 but inhibits CYP2D6 Inhibition of drug metabolism occurs in a dose related manner and can lead to toxicity of the object drug Blood flow limited metabolism Ex: Propranolol reduces rate of lignocaine metabolism by decreasing hepatic blood
ENZYME INHIBITION Example: ● Unexpected nausea/ vomiting, tremors in Theophylline with Erythromycin. ● QT prolongation-Torsades de pointes in Terfenadine with Ketoconazole ● L-dopa and Carbidopa - prevents peripheral decarboxylation ● Alcohol - Disulfiram (aldehyde dehydrogenase inhibitor) - aversion of alcohol Rang and Dale's pharmacology (Ninth edition)
Factors affecting biotransformation Biological factors : age, race, diet (neonates-glucuronyl transferase-grey baby syndrome-chloramphenicol) Concurrent use of drugs: Enzyme Induction & Inhibition Pathological status : Hepatitis, Hypothyroidism Pollutant exposure from environment or industry : pesticides, charcoal broiled meat Genetic polymorphism : Succinyl choline (Atypical pseudocholinesterase) - prolonged apnea due to retartded metabolism
Role of metabolism in drug discovery Two key elements in new drug development, efficacy and safety depend on drug biotransformation. Computer based (in silico) computation - Metabolomics In vitro - Human liver S9 fractions In vitro studies can give information about ● Metabolite stability ● Metabolite profile ● Metabolite identification ● CYP induction/ inhibition ● Drug-Drug interaction studies ● CYP isoform identification
Biotransformation.pptx
Recap Biotransformation aims to convert water insoluble drugs/ substances to water soluble form and is excreted through kidney/ bile Phase I reactions - addition of functional groups changes the biological property of the xenobiotic CYP 450 is the principal enzyme of phase I reactions Phase II reactions - phase I metabolite is conjugated to increase the water solubility Biotransformation can determine the efficacy and toxicity of a drug by controlling its biological t1/2
Recap Different factors influence the xenobiotic metabolism CYP inducers and inhibitors are the most important cause for drug-drug interactions Prediction of metabolism and ADRs by knowledge of biotransformation with modern In vitro and In silico methods are emerging as the most important in the new drug development process.
Reference Goodman, Louis S., Alfred Gilman, Laurence L. Brunton, John S. Lazlo, and Keith L. Parker. 2017. Goodman & Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill. Ritter, J. (2020). Rang and Dale's pharmacology (Ninth edition) Edinburgh: Elsevier. Tripathi, K. D. (2018). Essentials of medical pharmacology (8th edition). Jaypee Brothers Medical. Bertram G. Katzung , Todd W. Vanderah ,Basic & Clinical Pharmacology 15th Edition, McGraw-Hill Lange. Principles of Pharmacology by H. L. Sharma and K. K. Sharma; Paras Medical Publishers, New Delhi.2018. Illustrated reviews : Pharmacology by Karen Whalen, Lippincott, Wolters Kluwer
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Biotransformation.pptx

  • 1. BIOTRANSFORMATION (Metabolism of drugs) Dr. Arun kumar. R PGY1 Department of Pharmacology SRM MCH & RC
  • 2. OUTLINE ➢ Introduction ➢ Phases of metabolism ➢ Phase 1 metabolism ➢ Cytochrome P family ➢ Phase 2 metabolism ➢ First pass metabolism ➢ Microsomal drug induction ➢ Drug inhibition ➢ Factors affecting biotransformation ➢ Biotransformation in drug development ➢ Take home message
  • 3. Clinical vignette Q. A 68 year old woman is brought to the emergency for treatment of chest pain. She is currently taking aspirin and clopidogrel daily, as well as omeprazole for heartburn. What can be the most likely contributor to her symptoms?
  • 4. Biotransformation Chemical alteration of drug in the body that converts non polar or lipid soluble compounds to polar or lipid insoluble compounds Why does metabolism occur ? The many therapeutic agents that are lipophilic, hydrophobic do not pass readily into the aqueous environment of the urine, in the absence of metabolism, they accumulate in fat and cellular phospholipid bilayers Xenobiotics - substances foreign to the body, can be from natural or artificial sources.
  • 5. The metabolism of drugs and other xenobiotics into more hydrophilic metabolites is essential for termination of their biological, pharmacological activity and can easily be eliminated from the body through the urine or the bile Consequences: • Inactivation - Formation of an inactive metabolite from an active drug, that is readily excreted from the body (Ex: Phenobarbitone Hydroxyphenobarbitone) • Active metabolite from an active drug (Ex: Diazepam Oxazepam) • Activation of inactive drug (Generate biologically active metabolites, Ex: Levodopa) • Toxic to non toxic metabolite
  • 6. Sites : Liver, GI tract, Kidneys, Lungs, Plasma Liver: Major site (Eg: Morphine, Prazosin, Paracetamol, Lidocaine, Nitroglycerine) GIT: Insulin, Catecholamines, Salbutamol, Clonazepam, Chlorpromazine Lung: Prostanoids Plasma: Succinylcholine, Adenosine Placenta: Alcohol
  • 7. 1. Phase 1 reactions/ Non-synthetic [oxidation/ reduction/ hydrolysis, CYPs] Introduction of functional groups such as (–OH, –COOH, –O–, or NH2) and converts parent drug to more polar metabolite. 1. Phase 2 reactions/ Synthetic [conjugation] Conjugation reactions in which a covalent linkage is formed between a functional group on the parent compound or phase 1 metabolite and an endogenous substrate like glucuronic acid, sulfate, acetate or an amino acid. Biotransformation reactions
  • 8. Q. Which of the following reactions represents Phase II of drug metabolism ? a) Amidation b) Hydrolysis c) Oxidation d) Reduction e) Sulfation
  • 9. Phase 1 reactions/ Non-synthetic Phase 2 reactions/ Synthetic Biotransformation ● Oxidation ● Reduction ● Hydrolysis ● Cyclization ● Decyclization ● Glucuronide conjugation ● Acetylation ● Methylation ● Sulphate conjugation ● Glycine conjugation ● Glutathione conjugation ● Ribonucleoside or nucleotide synthesis
  • 10. Phase I Phase II oxidation/ reduction/ hydrolysis Drugs directly enter Phase II metabolism Conjugation drug is usually inactive After Phase I the drug may be activated, inactivated or unchanged DRUG/ XENOBIOTICS Conjugation products
  • 11. Biotransformation reactions Bertram G. Katzung , Todd W. Vanderah ,Basic & Clinical Pharmacology 15th Edition
  • 12. Metabolising enzymes Goodman & Gilman's the pharmacological basis of therapeutics
  • 13. Drug metabolising enzymes : Microsomal enzymes Site: These enzymes are present in the smooth endoplasmic reticulum of the liver, lungs, kidney and intestinal mucosa. Principal enzymes: Cytochrome P - 450 MFOs (mixed function oxidases) Microsomal enzymes are concerned with Phase 1 reactions - oxidation, reduction, hydrolysis and glucuronyl conjugation of Phase 2
  • 14. Goodman & Gilman's the pharmacological basis of therapeutics
  • 15. Phase 1 or Non synthetic reactions Oxidation: Addition of oxygen (negatively charged radical) or removal of hydrogen (positively charged radical) Reactions are carried out by a group of monooxygenases in the liver Important oxidation reactions are hydroxylation, oxygenation at C, N or S atoms, oxidative deamination etc., Microsomal oxidations - those catalysed by microsomal enzymes (CYP dependent)
  • 16. Multiple CYP gene families have been identified in humans and categorized based on protein sequence homology The cytochrome P-450 isoenzymes are identified and grouped into more than 20. Families - 1,2,3…. (CYP1) Most of the drug metabolising enzymes are in CYP 1,2 & 3 families. Subfamilies are identified as A, B & C… (CYP1A) An additional numeral when isoform is identified (CYP1A2) Italics indicate gene (CYP1A2); regular font is enzyme(CYP1A2) Isoenzyme families important in humans are CYP1, CYP2, CYP3 Cytochrome P family
  • 17. Cytochrome enzymes Goodman & Gilman's the pharmacological basis of therapeutics
  • 18. Carryout biotransformation of largest number (30- 50%) of drugs. In addition to liver, these isoforms are expressed in intestine (responsible for first pass metabolism at this site) and kidney as well. Example: Inhibition of CYP3A4 by erythromycin, ketoconazole etc., Rifampicin, phenytoin, carbamazepine are inducers of CYP3A4 CYP3A4/5
  • 19. Cytochromes : Metabolism of drugs Tripathi, K. D. (2018). Essentials of medical pharmacology (8th edition)
  • 20. Tripathi, K. D. (2018). Essentials of medical pharmacology (8th edition)
  • 21. Monoamine oxidase (MAO), Diamine oxidase (DAO) MAO (mitochondrial) oxidatively deaminates endogenous substrates including neurotransmitters. Dopamine, Serotonin, norepinephrine, epinephrine Alcohol & Aldehyde dehydrogenase Non-specific enzymes found in soluble fraction of liver Ethanol metabolism Flavin monooxygenases These enzymes are involved in metabolism of drugs like ranitidine Non CYP drug oxidations:
  • 22. This reaction is the converse of oxidation and involves cytochrome P-450 enzymes working in the opposite direction. Alcohols, aldehydes, quinones are reduced. Drugs primarily reduced are chloralhydrate, chloramphenicol, halothane, warfarin Reduction process catalysed by microsomal enzymes Reduction
  • 23. Site: Hydrolysis occurs in liver, intestines, plasma and other tissues. Microsomal hydrolysis: Hydrolytic reactions are rarely microsomal, except for Example: 1. Pethidine to Pethidinie acid (meperidinie) 2. Lidocaine hydrolysis Non -microsomal hydrolysis: Enzymes involved are esterases, amidases. Example: 1.Procaine to PABA by plasma choline esterases 2.Atropine to tropic acid 3.Hydrolysis of penicillin-G & procainamide by amidases Hydrolysis
  • 24. Cyclization Formation of a ring structure from a straight chain compound Ex: Proguanil Decyclization Opening up of ring structure of the cyclic drug molecule Ex: Barbiturates, Phenytoin Cyclization and Decyclization
  • 25. Conjugation of the drug or its phase I metabolite with an endogenous substrate To form a polar, highly ionized organic acid, which is easily excreted in urine or bile Conjugation reactions have high energy requirement and are generally faster than phase 1 reactions Phase 2 reactions/ Synthetic [conjugation]
  • 26. • Carried out by a group of UDP-glucuronosyl transferases (UGTs) • Compounds with a phenolic, alcoholic, hydroxyl or carboxylic acid group are easily conjugated with glucuronic acid Example: • Chloramphenicol, aspirin, paracetamol, diazepam, lorazepam, morphine • Other than drugs, endogenous substrates like bilirubin, steroidal hormones and thyroxine utilize this and gets excreted in the bile Drug glucuronides excreted in bile can be hydrolysed by bacteria in the gut- the liberated drug is reabsorbed and undergoes the same fate. This enterohepatic cycling of the drug prolongs its action. Example: oral contraceptives. Glucuronide conjugation: [Microsomal conjugation]
  • 27. Non –microsomal conjugation N-Acetyl conjugation Site: Cytoplasm Catalysed by N-Acetyl transferase using acetyl coenzyme-A Important in sulfonamide metabolism because acetyl-sulfonamides are less soluble than the parent compound and may cause renal toxicity due to precipitation in kidney. Example : Isoniazid, Dapsone, Sulfonamides, Histamine
  • 28. Sulfate conjugation Site: Cytoplasm Major pathway for phenols, also occurs for alcohol, amines Catalysed by Sulfotransferases using PAPS (3-phosphoadenosine-5-phosphosulfate) Infants and young children have predominating O-sulfate conjugation Example : Aspirin, Paracetamol, Corticosteroids, Methyldopa, Chloramphenicol
  • 29. Non–microsomal conjugation : Minor metabolic pathways Amino acid conjugation: Site: mitochondria • ATP dependent acid: CoA ligase forms CoA-amino acid conjugates which then react with drugs by N-Acetylation • Drugs like Nicotinic acid, Aspirin, Benzoic acid, Glycine, Arginine Methyl conjugation: Site: cytoplasm • Drugs like Dopamine, Epinephrine, Histamine are catalysed by enzyme transmethylase with S-adenosine methionine
  • 30. Minor metabolic pathways - contd.. Glutathione conjugation: Glutathione is a protective factor for removal of potentially toxic compounds Site: cytoplasm Drugs like ethacrynic acid, sulfobromophthalein, Paracetamol are catalysed by enzyme g- glutamyl transpeptidase - the products can be further acetylated to N-acetylcysteine conjugate. Example: Paracetamol Ribosides and Riboside Phosphates: Purines & pyrimidines, used as antimetabolites in chemotherapy, form their active metabolites by forming ribonucleosides and ribonucleotides.
  • 31. Phase II reactions • Some drugs are directly metabolised by phase II reactions, before phase I • Same drugs can be metabolised by different enzymes simultaneously Ex: Amitriptyline metabolised by CYP2D6, CYP2C9, CYP2C19 • Same CYP can metabolise different drugs simultaneously Ex: CYP3A4 can bind metabolize diazepam and testosterone simultaneously Isoniazid Hydrolysis (phase I) N-acetyl conjugate (phase II)
  • 32. Spontaneously metabolised in plasma through molecular rearrangement No enzyme action involved Example: Atracurium (skeletal muscle relaxant) Non-enzymatic Biotransformation HOFMANN ELIMINATION
  • 33. First Pass Metabolism/ Pre - systemic elimination/ First pass effect Metabolism of a drug during its passage from the site of absorption into the systemic circulation. Occurs for drugs that are taken orally. • Significant amount of drug is inactivated before reaching systemic circulation • Certain amount of drug is absorbed as it passes through GIT wall and portal circulation. • Decreased bioavailability of the drug • Diminished therapeutic effect • Bypassed by parenteral administration of drug - intravenous and sublingual.
  • 34. Attributes of drugs with high first pass metabolism • Oral dose is considerably higher than sublingual or parenteral dose • Marked individual variation in the oral dose due to differences in the extent of first pass metabolism • Oral bioavailability of a drug is increased if another drug is competing with it • Oral bioavailability is apparently increased in patients with severe liver disease Example: Propranolol Principles of Pharmacology by H. L. Sharma and K. K. Sharma
  • 35. Microsomal enzyme induction • A number of drugs, many carcinogenic chemicals and insecticides on repeated administration increase the synthesis of microsomal enzyme protein i.e increase the rate of metabolism. • As this requires synthesis of proteins, induction takes 4 - 14 days to reach its peak and equal time to dissipate after the enzyme inducer is stopped.
  • 36. Different inducers are selective for certain forms of cytochrome P-450 enzyme CYP3A is induced by - Antiepileptic drugs : Phenobarbitone, Rifampicin and Glucocorticoids. CYP2E1 is induced by - Isoniazid, Chronic alcohol consumption CYP1A is induced by - Cigarette smoking, Industrial pollutants, Charcoal broiled meat
  • 37. ENZYME INDUCTION Principles of Pharmacology by H. L. Sharma and K. K. Sharma
  • 38. Clinical relevance of enzyme induction Decreased intensity of therapeutic effect of the drug. Example: Failure of Oral contraceptive pills, Warfarin if enzyme inducers like phenytoin or rifampicin are used concomitantly. Smoking (polycyclic aromatic hydrocarbons) and theophylline. Increased intensity of therapeutic effect of the drug. Example: Hepatotoxicity from paracetamol in alcoholics
  • 39. Tolerance - autoinduction Example: Barbiturates, Carbamazepine enhance their own metabolism leading to tolerance. Interfere with adjustment of dose of another drug and side effects like osteomalacia. Therapeutic benefits: The knowledge of enzyme induction can also be used for therapeutic benefits Example: To treat neonatal jaundice - Phenobarbitone
  • 40. Inhibition of metabolism One drug may competitively inhibit the metabolism of another drug - if it utilizes same enzyme Unlike induction it is a rapid process and usually reversible A drug may inhibit one isoenzyme while being itself a substrate for another isoenzyme. Example: Quinidine - metabolised by CYP3A4 but inhibits CYP2D6 Inhibition of drug metabolism occurs in a dose related manner and can lead to toxicity of the object drug Blood flow limited metabolism Ex: Propranolol reduces rate of lignocaine metabolism by decreasing hepatic blood
  • 41. ENZYME INHIBITION Example: ● Unexpected nausea/ vomiting, tremors in Theophylline with Erythromycin. ● QT prolongation-Torsades de pointes in Terfenadine with Ketoconazole ● L-dopa and Carbidopa - prevents peripheral decarboxylation ● Alcohol - Disulfiram (aldehyde dehydrogenase inhibitor) - aversion of alcohol Rang and Dale's pharmacology (Ninth edition)
  • 42. Factors affecting biotransformation Biological factors : age, race, diet (neonates-glucuronyl transferase-grey baby syndrome-chloramphenicol) Concurrent use of drugs: Enzyme Induction & Inhibition Pathological status : Hepatitis, Hypothyroidism Pollutant exposure from environment or industry : pesticides, charcoal broiled meat Genetic polymorphism : Succinyl choline (Atypical pseudocholinesterase) - prolonged apnea due to retartded metabolism
  • 43. Role of metabolism in drug discovery Two key elements in new drug development, efficacy and safety depend on drug biotransformation. Computer based (in silico) computation - Metabolomics In vitro - Human liver S9 fractions In vitro studies can give information about ● Metabolite stability ● Metabolite profile ● Metabolite identification ● CYP induction/ inhibition ● Drug-Drug interaction studies ● CYP isoform identification
  • 45. Recap Biotransformation aims to convert water insoluble drugs/ substances to water soluble form and is excreted through kidney/ bile Phase I reactions - addition of functional groups changes the biological property of the xenobiotic CYP 450 is the principal enzyme of phase I reactions Phase II reactions - phase I metabolite is conjugated to increase the water solubility Biotransformation can determine the efficacy and toxicity of a drug by controlling its biological t1/2
  • 46. Recap Different factors influence the xenobiotic metabolism CYP inducers and inhibitors are the most important cause for drug-drug interactions Prediction of metabolism and ADRs by knowledge of biotransformation with modern In vitro and In silico methods are emerging as the most important in the new drug development process.
  • 47. Reference Goodman, Louis S., Alfred Gilman, Laurence L. Brunton, John S. Lazlo, and Keith L. Parker. 2017. Goodman & Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill. Ritter, J. (2020). Rang and Dale's pharmacology (Ninth edition) Edinburgh: Elsevier. Tripathi, K. D. (2018). Essentials of medical pharmacology (8th edition). Jaypee Brothers Medical. Bertram G. Katzung , Todd W. Vanderah ,Basic & Clinical Pharmacology 15th Edition, McGraw-Hill Lange. Principles of Pharmacology by H. L. Sharma and K. K. Sharma; Paras Medical Publishers, New Delhi.2018. Illustrated reviews : Pharmacology by Karen Whalen, Lippincott, Wolters Kluwer

Editor's Notes

  1. (zoles, mycins, CCBs, antihistamines)