4. Introduction
Polymorphism : Genetic difference 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
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5. CAUSES
Balance between variations created by new mutation and natural
selection
Frequency dependent selection
Multiple niche polymorphism
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10. VARIATION IN PHASE I
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
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11. DIFFERENT ALLELIC AND
PHENOTYPIC VARIANTS OF
CYP2D6
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S.NO
O
PHENOTYPE ALLELIC VARIANTS
1 POOR METABOLISER
METABOLISER
CYP2D6
2 INTERMEDIATE
METABOLISER
CYP2D9
3 ULTRARAPID
METABOLISER
CYP2D1
12. EXAMPLES
1. TAMOXIFEN IN BREAST 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 .
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13. 3. CLOPIDOGREL AS ANTIPLATELET 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
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14. VARIATIONS IN PHASE 2
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
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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
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