Prior to a more detailed discussion on the practical applications of pharmacogenetics and pharmacogenomics in cardiovascular pharmacotherapy, knowledge of the major biotransformational and transport pathways is required Detailed herein is a brief summary of the most common enzymes and proteins involved in the disposition of cardiovascular-related drugs (a more comprehensive list of other contributing enzymes and proteins is summarized in Tables 79.1 and 79.2) If known, information on allelic variation and ontogeny is included Table 79.1 Drug-Metabolizing Enzymes Enzyme/Gene Locationa CYP1A2 Liver, colon (rare) Substratesb Caffeine, propranolol, verapamil, R-warfarin CYP2B6 Liver, lung Ketamine, methadone, propofol CYP2C8 CYP2C9 Liver Liver, small intestine CYP2C19 Liver, small intestine (rare) CYP2D6 Liver, lung (rare), brain (rare), small intestine (rare) Cerivastatin, torsemide NSAIDs: diclofenac, ibuprofen, S-naproxen ARBs: losartan, irbesartan Others: fluvastatin, torsemide, S-warfarin PPIs: esomeprazole, lansoprazole, omeprazole, pantoprazole Others: clopidogrel, indomethacin, labetalol, propranolol, R-warfarin Antiarrhythmics: flecainide, mexiletine, procainamide, propafenone β-blockers: atenolol, carvedilol, metoprolol, propranolol, timolol Other: clonidine Benzodiazepines: alprazolam, midazolam Calcium channel blockers: amlodipine, diltiazem, felodipine, nifedipine, verapamil CYP3A4/5/7 3A4: Liver, small intestine, lung (rare), stomach (rare), Inhibitorsb Cimetidine,d ciprofloxacin,e fluvoxaminee Clopidogrel Gemfibrozil,e trimethoprimf Amiodarone,f fluconazole,e fluvastatin Cimetidine, esomeprazole, lansoprazole, omeprazole, pantoprazole Inducersb Omeprazole, rifampin, tobacco Phenobarbital, phenytoin, rifampin, Rifampin Rifampin Rifampin Amiodarone,d bupropion,e cimetidine,d fluoxetine,e paroxetine,e quinidine,e sertraline,f terbinafinef Cimetidine,d clarithromycin,e diltiazem,f erythromycin,f fluconazole,f grapefruit juice,f ketoconazole,e indinavir,e itraconazole,e ritonavir,g verapamilf Barbiturates, carbamazepine, efavirenz, nevirapine, phenytoin, rifampin, ritonavir,g St colon (rare) 3A5: Liver, lung UGT1A1c Liver UGT1A3c UGT2B7c Liver Liver HMG-CoA reductase inhibitors: atorvastatin, lovastatin, simvastatin Immunosuppressives: cyclosporine, tacrolimus, sirolimus Others: erythromycin, midazolam, quinidine, sildenafil, tadalafil Bilirubin, carvediol, Atazanavir, indinavir, simvastatin sorafenib Atorvastatin Gemfibrozil Codeine, morphine, lorazepam, propranolol John's wort aCYP location summarized from Zanger UM, Schwab M Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation Pharmacol Ther 2013;138(1):103–141 and Paine MF, Hart HL, Ludington SS, et al The human intestinal cytochrome P450 “pie” Drug Metab Dispos 2006;34(5):880–886 bData from http://medicine.iupui.edu/clinpharm/ddis/main-table cUGT data summarized from de Wildt SN, Kearns GL, Leeder JS, van den Anker JN Glucuronidation in humans Pharmacogenetic and developmental aspects Clin Pharmacokinet 1999;36(6):439–452 dWeak inhibitor eStrong inhibitor fModerate inhibitor g Can be both an inhibitor and an inducer ARBs, Angiotensin receptor blockers; NSAIDs, nonsteroidal antiinflammatory drugs; PPIs, proton pump inhibitors Table 79.2 Drug Transporters Gene Family SLCO Protein Location Substrates Role OATP1A2 Brain, kidney, liver OATP1B1 Liver Indomethacin CNS distribution OATP1B3 Liver Digoxin, olmesartan, rosuvastatin, telmisartan, valsartan Digoxin, fluvastatin OATP2B1 Liver, intestine, placenta Atorvastatin, bosentan, enalapril, Hepatic uptake pravastatin, rosuvastatin, simvastatin acid Hepatic uptake Hepatic uptake, oral absorption SLC10A1 NTCP Liver SLC22 Kidney, brain Kidney, brain Kidney, placenta Liver, brain, small intestine Kidney, brain, small intestine Heart, skeletal muscle, liver, adrenal Kidney, liver Kidney Liver OAT1 OAT3 OAT4 OCT1 OCT2 OCT3 SLC47 ABCB MATE1 MATE2 BSEP P-gp (MDR1) ABCC MRP1 MRP2 MRP3 ABCG MRP4 BCRP Atorvastatin, fluvastatin, pitavastatin, rosuvastatin Acyclovir Salicylates, valacyclovir Hepatic uptake Quinidine, verapamil Renal uptake Renal uptake Renal secretion Hepatic and renal uptake Dopamine, norepinephrine Renal uptake Epinephrine, norepinephrine Renal secretion, biliary excretion Renal secretion Lovastatin, pravastatin, rosuvastatin, Biliary secretion simvastatin Cyclosporine, digoxin, Oral absorption, biliary erythromycin, simvastatin excretion, renal secretion, CNS distribution Kidney, liver, brain, small intestine Liver, small intestine, kidney, brain Liver, kidney, Pravastatin small intestine Liver, kidney, small intestine Liver, kidney Liver, small Pravastatin intestine, placenta Biliary excretion, renal secretion Oral absorption, biliary excretion Data from Ho RH, Kim RB Transporters and drug therapy: implications for drug disposition and disease Clin Pharmacol Therap 2005;78(3):260–277; 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