1. ?

2. MORE GENETICS OF PK AND PD Lecture #28

4. Inherited Variability Restricted to drug metabolism ~None with drug absorption, distribution, renal or biliary excretion – Exception: organic anion-transporting polypeptide 1B1 (OATP1B1)  pravastatin

5. Mutation Types Non-synonymous substitution – alters amino acid of protein synonymous substitution – “silent mutation” and degeneracy – doesn’t alter amino acid

6. Basic Genetics intron “Between Genes”

8. Inherited Variability in PK Oxidation – CYP2D6 – CYP2C9 – CYP2C19 – CYP3A S-methylation – Thiopurine methyltransferase (TMPT) Acetylation – N-acetyltranferase (NAT)

9. Oxidation: CYP2C9 African Pygmy

10. Oxidation: CYP2C9

12. Oxidation: CYP2C19 (PPI)

13. Oxidation: CYP2C19 Polymorphisms

14. Oxidation: CYP2C19

15. CYP2C19: Proton Pump Inhibitor Therapy

16. Oxidation: CYP3A

17. S-methylation: Thiopurine Methyltransferases (TPMT) SAM 6-thioguanine

18. S-methylation: Reaction 6-thioguanine 6-methylthioguanine TPMT S-adenosyl methionine S-adenosyl-L-homocysteine CH 3 antimetabolites (anticancer drug)

19. Polymorphisms

20. S-methylated Drugs Pharmacodynamics HGPRT= Hypoxanthine-guanine phosphoribosyltransferase immunosuppressant (organ transplantation) cancer, Crohn’s disease and ulcerative colitis Target inhibit cell proliferation leukemia Purine Biosynthesis

21. Conventional versus Individualized Individualized Conventional

22. Acetylation: N-acetyltransferases (NAT) Acetyl-CoA

23. General Reaction NAT R R

24. Reactions (Sim, 2008 Toxicology)

25. Families, Location and General Substrate Specificities NAT1 – everywhere – folate degradation – breast cancer NAT2 – Liver and Gut – sulfamethazine and arylhydrazine – isoniazid induced neurotoxicity and hydralazine-induced lupus (slow metabolizers) sulfamethazine (sulfonamide antibacterial) arylhydrazine

26. Genetics: Polymorphic Variants NAT2NAT1

27. NAT2 KatG = Bacterial Catalase-peroxidase InhA = Bacterial 2-trans-enoyl-acyl carrier protein reductase tuberculosis antibiotic

28. NAT2

29. Metabolic Profiling