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INTRODUCTION TO BIOTRANSFORMATION OF DRUG (METABOLISM OF PHENYTOIN AND CODEINE)

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INTRODUCTION TO BIOTRANSFORMATION OF DRUG (METABOLISM OF PHENYTOIN AND CODEINE)

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INTRODUCTION TO BIOTRANSFORMATION OF DRUG (METABOLISM OF PHENYTOIN AND CODEINE)

  1. 1. INTRODUCTION TO BIOTRANSFORMATION OF DRUG (EG METABOLISM OF PHENYTOIN AND CODEINE ) PRESENTED BY ADAM SHAHUL HAMEED M.TECH COMPUTATIONAL BIOLOGY
  2. 2. INTRODUCTION  Biotransformation means chemical alteration of the drug in the body.  Biotransformation is a major mechanism for drug elimination.  Enzymatic processes in liver and other tissues that modify the chemical structure of drugs render them more water-soluble, increase their elimination, decrease their half-life.  Biotransformed metabolites are chemically different from the parent molecule  Metabolism makes the compound less lipid soluble and more polar and thus hydrophilic.
  3. 3. TYPES OF METABOLIC TRANSFORMATION There are two phases in the metabolism of drugs:-  Phase 1 reaction. (Non synthetic phase).  This involves a change in drug molecule. It involves oxidation, reduction or hydrolysis. This may result in activation, change or inactivation of drug.  Phase II reaction. (Synthetic phase)  It involves formation of conjugates with drug or its metabolites formed in phase 1 reaction. The conjugate is formed with an endogenous substance such as carbohydrates and amino acids.
  4. 4. OXIDATION  Loss of electrons M = M+ + e-  Gain of oxygen R + O = RO  Hydroxylation; Oxygenation at C,N and S atoms;N or O dealkylation, oxidative deamination
  5. 5. CYTOCHROME P-450 MONOOXYGENASE (MIXED FUNCTION OXIDASE)  A large number of families (at least 18 in mammals) of cytochrome P-450 (abbreviated “CYP”) enzymes exists  Each member of which catalyzes the biotransformation of a unique spectrum of drugs. some overlap in the substrate specificities.  This enzyme system is the one most frequently involved in phase I reactions.
  6. 6. CYTOCHROME P-450 MONOOXYGENASE (MIXED FUNCTION OXIDASE)  Heme protein  Terminal oxidase of the mixed-function oxidase (MFO) electron-transfer system  Located in the smooth endoplasmic reticulum of all major organs and tissues  Uses NADPH as a source of reducing equivalents
  7. 7. THE P450 GENE SUPERFAMILY  Format of nomenclature: CYPFamily/Subfamily/Gene  The cytochrome P-450 families are referred to using an arabic numeral, e.g., CYP1, CYP2, etc.  Each family has a number of subfamilies denoted by an upper case letter, e.g., CYP2A, CYP2B, etc.  The individual enzymes within each subfamily are denoted by another arabic numeral, e.g., CYP3A1, CYP3A2, etc.
  8. 8. Localization  The primary location of cytochrome P-450 is the liver,  Liver is the major organ of biotransformation  Kidney, Lungs, testes, skin intestines are the secondary organ of biotransformation.  Other tissues, including:  the adrenals  ovaries and testis  tissues involved in steroidogenesis and steroid metabolism.  The enzyme's subcellular location is the endoplasmic reticulum.
  9. 9. Mechanism of reaction In the overall reaction:  the drug is oxidized  oxygen is reduced to water.  Reducing equivalents are provided by nicotinamide adenine dinucleotide phosphate (NADPH), and generation of this cofactor is coupled to cytochrome  Most of the reactions of cytochromeP450 involve the addition of a hydroxyl group to a compound which may be represented as
  10. 10. REDUCTION  Gain of electrons M+ + e- = M  Loss of oxygen RO = R + O  Gain of hydrogen R + H = RH
  11. 11. REDUCTION  Nitro to amino group NO2 NO HNOH HNH  Chromium VI to Chromium III Cr6+ + 3 e- Cr3+
  12. 12. CYCLIZATION AND DECYCLIZATION Cyclization This is formation of ring structure from a straight chain compound, e.g. proguanil. De cyclization This is opening up of ring structure of the cyclic drug molecule, e.g. barbiturates, phenytoin.
  13. 13. SYNTHETIC REACTIONS (PHASE 2 METABOLISM)  These involve conjugation of the drug or its phase I metabolite with an endogenous substrate, generally derived from carbohydrate or amino acid, to form a polar highly ionized organic acid, which is easily excreted in urine or bile  Conjugation reactions have high energy requirement  For conjugation to take place, a compound should have an appropriate group or centre eg – COOH, -OH, -NH, or –SH.  Conjugated metabolites are in variably less lipid soluble than their parent compound
  14. 14. GLUCURONIDE CONJUGATION  This is the most important synthetic reaction carried out by a group of UDP-glucuronosyl transferases (UGTs).  Compounds with a hydroxyl or carboxylic acid group are easily conjugated with glucuronic acid which is derived from glucose.  Examples are chloramphenicol, aspum, paracetamol, lorazepam, morphine, metronidazole.  Not only drugs but endogenous substrates like bilirubin, steroidal hormones and thyroxine utilize this pathway.
  15. 15. Acetylation  Compounds having amino or hydrazine residues are conjugated with the help of acetyl coenzyme-A, e.g. sulfonamides, isoniazid, PAS, hydralazine, clonazepam, procainamide. Methylation  The amines and phenols can be methylated; methionine and cysteine acting as methyl donors, e.g. adrenaline, histamine, nicotinic acid, methyldopa, captopril
  16. 16. SULFATE AND GLYCINE CONJUGATION Sulfate conjugation The phenolic compounds and steroids are sulfated by sulfotransferases (SULTs). e.g. chloramphenicol, methyldopa, adrenal and sex steroids. Glycine conjugation Salicylates and other drugs having carboxylic acid group are conjugated with glycine, but this is not a major pathway of metabolism.
  17. 17. Glutathione conjugation:  Forming a mercapturate is normally a minor pathway. However, it serves to inactivate highly reactive quinone or epoxide intermediates formed during metabolism of certain drugs, e.g. paracetamol.  When large amount of such intermediates are formed (in poisoning or after enzyme induction), glutathione supply falls short-toxic adducts are formed with tissue constituents to tissue damage. Ribonucleoside/nucleotide synthesis:  This pathway is important for the activation of many purine and pyrimidine antimetabolites used in cancer chemotherapy.
  18. 18. MICROSOMAL ENZYMES  These are located on smooth endoplasmic reticulum (a system or microtubules inside the cell), primarily in liver, also in kidney, intestinal mucosa and lungs.  The monooxygenases, cytochrome P 450, glucuronyl transferase, etc. are microsomal enzymes. They catalyse most of the oxidations, reductions, hydrolysis and glucuronide conjugation Microsomal enzymes are inducible by drugs, diet and other agencies.
  19. 19. NONMICROSOMAL ENZYMES  These are present in the cytoplasm and mitochondria of hepatic cells as well as in other tissues including plasma  The flavoprotein oxidases, esterases, amidases and conjugases are nonmicrosomal enzymes. Reactions catalysed are:  Some oxidations and reductions, many hydrolytic reactions and all conjugations except-glucuronidation.
  20. 20. 1. Cytochrome P-450 2. Alcohol dehydrogenase 3. Deaminases 4. Esterases 5. Amidases 6. Epoxide hydratases 1. Glucuronyl transferase (glucuronide conjugation) 2. Sulfotransferase (sulfate conjugation) 3. Transacylases (amino acid conjugation) 4. Acetylases 5. Ethylases 6. Methylases 7. Glutathione transferase. Enzymes catalyzing phase I biotransformation Enzymes catalyzing phase II biotransformation
  21. 21. HOFMANN ELIMINATION  This refers to inactivation of the drug in the body fluids by spontaneous molecular rearrangement without the agency of any enzyme, e.g. atracurium.
  22. 22. RESULTS OF BIOTRANSFORMATION  Production of metabolites that are more polar than the parent drug  Usually terminates the pharmacologic action of the parent drug  After phase I reactions, similar or different pharmacologic activity, or toxicologic activity.
  23. 23. METABOLISM OF DRUG LEADS TO  Inactivation of drug: The active drug is converted in to inactive metabolites & excreted. Ex-lidocaine, ibuprofen. Also conversion of phenytoin to p-hydroxy phenytoin.  Active metabolites from equally active metabolites: The drug is converted in to similar active metabolites. Ex- conversion of codeine in to morphine, having similar activity.  Active metabolites from inactive drug (prodrug): Some drugs given in the form of inactive form which are made active by metabolism. Ex- enalapril which activated in the form of enalaprilat, which is prodrug.
  24. 24. METABOLISM OF DRUG LEADS TO  Conversion in to toxic substances: Xenobiotics metabolizing enzymes are responsible for elimination of drug but may convert it in to toxic metabolites.  This occurs when the enzyme convert the drug in to unstable intermediate which has affinity towards cellular component & causing toxic effect.  They have carcinogenic activity, when the electron deficient atom is formed which reacted with DNA & RNA of the cell and causing mutation of gene. Other ex- conversion of paracetamol to toxic metabolite causing hepatic toxicity.
  25. 25. PHENYTOIN EPILEPSY: It is a Chronic medical condition produced by sudden changes in the electrical function of the brain.
  26. 26. METABOLISM OF PHENYTOIN
  27. 27. Pharmacokinetics of phenytoin  Well absorbed when given orally, however, it is also available as iv. (for emergency)  80-90% protein bound  Induces liver enzymes (Very Important)  Metabolized by the liver to inactive metabolite  Metabolism shows saturation kinetics and hence t ½ increases as the dose increased  Excreted in urine as glucuronide conjugate  Plasma t ½ approx. 20 hours  Therapeutic plasma concentration 10-20 μg/ml (narrow)  Dose 300-400 mg/day
  28. 28. CODEINE  Codeine or 3methylmorphine (a naturally occurring methylated morphine) is an opiate used for its analgesic, antidiarrheal, antihypertensive, anxiolytic, antidepressant, sedative and hypnotic properties.  Codeine is used to treat mild to moderate pain and to relieve cough.
  29. 29. METABOLISM OF CODEINE
  30. 30. METABOLISM OF CODEINE
  31. 31.  REFERENCE 1.Essential of medical Pharmacology by K.D Tripathi and Jaypee page no 23 to 30 2.Biochemistry by U.Sathya narayana and U.Chakrapani. 3.Modern Pharmacology with Clinical applications by Lipinncott (Sixth Edition ) 4.Pharmacy Tutor www.pharmatutor.com 5.Wikipedia Biotransformation of Drug.  My Sincere Thanks to SHRIKANTH (Comp Bio )

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