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POLYMORPHISM AFFECTING DRUG METABOLISM.pptx
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- 3. Introduction Causes Types Drug metabolism andits types Variation in phase I with examples Variation in phase II with examples Presentation title 3 CONTENT
- 4. Introduction Polymorphism : Geneticdifference in drug metabolism are the result of genetically based variation in alleles for gene that code for enzyme responsible for the metabolism of drug . It contains abnormal pairs / multiple /abnormal gene leading to altered enzyme function . Drug Metabolism : Also called Biotransformation . Any chemical alteration of the drug in the body is known as Biotransformation .It covert lipid soluble substance into lipid insoluble substance. SITES of METABOLISM Major site --- Liver Other site of metabolism are : GIT, Lungs ,Kidney,Plasma,Skin , Nasal Mucosa Presentation title 4
- 5. CAUSES Balance between variationscreated by new mutation and natural selection Frequency dependent selection Multiple niche polymorphism Presentation title 5
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- 10. VARIATION IN PHASEI METABOLISM CYTOCHROME P4502D6 • Heme containing enzyme • Superfamily is very large • Represents diverse group of enzyme • Responsible for 20-25 % of drugs metabolism like – Antidepressant , Antiarrthymic drugs , Antipsychotic drugs etc • It has largest phenotypic variations • Have more than 80 allelic variations Presentation title 10
- 11. DIFFERENT ALLELIC AND PHENOTYPICVARIANTS OF CYP2D6 Presentation title 11 S.NO O PHENOTYPE ALLELIC VARIANTS 1 POOR METABOLISER METABOLISER CYP2D6 2 INTERMEDIATE METABOLISER CYP2D9 3 ULTRARAPID METABOLISER CYP2D1
- 12. EXAMPLES 1. TAMOXIFEN INBREAST CANCER : Metabolised by these enzymes to form endoxifen . More potent estrogen receptor . The anticancer property of tamoxifen has been largely attributed to this metabolite . It has been found that patients with poor metaboliser phenotype of CYP2D6 have lower level of endoxifen . There are more chance of relapse of cancer in these person 2. CODEINE IN POSTGESTATIONAL WOMEN AS ANALGESIC : Codeine – postgestational women –control pain due to child birth –less quantity excreated in breast milk . In ultra rapid metaboliser high level of morphine are detected in neonates which is fatal . Presentation title 12
- 13. 3. CLOPIDOGREL ASANTIPLATELET DRUG : Prodrug – metabolised by CYP2C19 –form active metabolite . Hence its variants form CYP2C19*17 – not metabolizes to active form – antiplatelet effect is not observed 4 OMEPRAZOLE IN PEPTIC ULCER 5. WARFARIN AS ANTICOAGULANTOMEPRAZOLE ETC Presentation title 13
- 14. VARIATIONS IN PHASE2 METABOLISM 1. N-METHYL TRANSFERASE –Variation on this enzyme has been seen in antituberculosis drugs like isoniazid Decrease metabolism of isoniazid in slow acetylator ( variants with decrease N ACETYL TRANSFERASE activity ) leads to neuritis (inflammation of one or more nerve ). Also leads to systemic lupus erythematous 1 Presentation title 14
- 15. 2. THIOPURINE METHYLTRANSFERASE(TPMT): Purine analogue ( example: 6 – mercaptopurine ) Treat heamatologic malignancies Convert into thioguanine nucleotide Incorporate in DNA strands DNA damage Thioguanine nucleotide metabolised by enzyme tpmt Increase in the level of thioguanine and low level of tpmt = Neutopenia Decrease anticancer activity of purine analogues Presentation title 15
- 16. Thank you MADHUVASHISHT