? MORE GENETICS OF PK AND PD Lecture #28 Inherited Variability Restricted to drug metabolism ~None with drug absorption, distribution, renal or biliary excretion Exception: organic anion-transporting polypeptide 1B1 (OATP1B1) pravastatin Mutation Types Non-synonymous substitution alters amino acid of protein synonymous substitution silent mutation and degeneracy doesnt alter amino acid Basic Genetics intron Between Genes Inherited Variability in PK Oxidation CYP2D6 CYP2C9 CYP2C19 CYP3A S-methylation Thiopurine methyltransferase (TMPT) Acetylation N-acetyltranferase (NAT) Oxidation: CYP2C9 African Pygmy Oxidation: CYP2C9 Oxidation: CYP2C19 (PPI) Oxidation: CYP2C19 Polymorphisms Oxidation: CYP2C19 CYP2C19: Proton Pump Inhibitor Therapy Oxidation: CYP3A S-methylation: Thiopurine Methyltransferases (TPMT) SAM 6-thioguanine S-methylation: Reaction 6-thioguanine 6-methylthioguanine TPMT S-adenosyl methionine S-adenosyl-L-homocysteine CH 3 antimetabolites (anticancer drug) Polymorphisms S-methylated Drugs Pharmacodynamics HGPRT= Hypoxanthine-guanine phosphoribosyltransferase immunosuppressant (organ transplantation) cancer, Crohns disease and ulcerative colitis Target inhibit cell proliferation leukemia Purine Biosynthesis Conventional versus Individualized Individualized Conventional Acetylation: N-acetyltransferases (NAT) Acetyl-CoA General Reaction NAT R R Reactions (Sim, 2008 Toxicology) 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 Genetics: Polymorphic Variants NAT2NAT1 NAT2 KatG = Bacterial Catalase-peroxidase InhA = Bacterial 2-trans-enoyl-acyl carrier protein reductase tuberculosis antibiotic NAT2 Metabolic Profiling