0031-6997/06/5803-521–590$20.00 PHARMACOLOGICAL REVIEWS Vol. 58, No. 3 Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics 60305/3134736 Pharmacol Rev 58:521–590, 2006 Printed in U.S.A Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice SHARON J. GARDINER AND EVAN J. BEGG Department of Medicine, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand Abstract ............................................................................... 523 I. Introduction/perspective ................................................................. 523 A. Background on pharmacogenetics ..................................................... 524 B. Pathways with genetic variation that may be important clinically ........................ 526 II. Cytochrome P450 ....................................................................... 526 A. CYP2D6 ............................................................................ 526 1. Tricyclic antidepressants .......................................................... 526 a. Amitriptyline (tertiary)/nortriptyline (secondary) .................................. 529 b. Imipramine (tertiary)/desipramine (secondary).................................... 530 c. Clomipramine (tertiary)/desmethylclomipramine (secondary) ....................... 531 d. Doxepin (tertiary)/desmethyldoxepin (secondary) .................................. 531 2. Selective serotonin reuptake inhibitors.............................................. 531 a. Fluoxetine .................................................................... 531 b. Paroxetine .................................................................... 531 c. Other selective serotonin reuptake inhibitors ..................................... 531 3. Other antidepressants............................................................. 532 a. Maprotiline ................................................................... 532 b. Mianserin ..................................................................... 532 c. Venlafaxine ................................................................... 532 4. Antidepressants (in general) and clinical outcomes ................................... 532 5. Antipsychotics.................................................................... 533 a. Chlorpromazine................................................................ 533 b. Haloperidol.................................................................... 533 c. Perphenazine.................................................................. 533 d. Thioridazine................................................................... 533 e. Zuclopenthixol ................................................................. 534 f. Atypical antipsychotics ......................................................... 534 g. Antipsychotics (in general) and clinical outcomes.................................. 534 6. Antiarrhythmics .................................................................. 534 a. Propafenone ................................................................... 535 b. Flecainide..................................................................... 535 c. Mexiletine .................................................................... 535 7. ␤-blockers........................................................................ 535 a. Carvedilol ..................................................................... 535 b. Metoprolol .................................................................... 536 c. Propranolol.................................................................... 536 d. Timolol ....................................................................... 537 8. Opioid analgesics ................................................................. 537 a. Codeine ....................................................................... 537 b. Dihydrocodeine ................................................................ 537 c. Tramadol ..................................................................... 538 Address correspondence to: Sharon Gardiner, Department of Medicine, Christchurch School of Medicine, Private Bag 4345, Christchurch, New Zealand. E-mail: sharon.gardiner@cdhb.govt.nz Funding was via a Top Achiever Doctoral (Tertiary Education Commission, New Zealand) scholarship (to S.G.). Article, publication date, and citation information can be found at http://pharmrev.aspetjournals.org. doi:10.1124/pr.58.3.6. 521 522 GARDINER AND BEGG d. Other opioids .................................................................. 538 9. Antiemetics ...................................................................... 538 10. Antihistamines ................................................................... 538 11. Other drugs ...................................................................... 538 a. Atomoxetine................................................................... 538 b. Perhexiline.................................................................... 539 c. Phenformin ................................................................... 539 d. Tolterodine.................................................................... 539 12. Summary of CYP2D6 ............................................................. 539 B. CYP2C9 ............................................................................ 540 1. Coumarin anticoagulants .......................................................... 541 a. Warfarin ...................................................................... 542 b. Acenocoumarol ................................................................ 543 c. Phenprocoumon................................................................ 543 2. Sulfonylurea drugs................................................................ 543 a. Tolbutamide................................................................... 543 b. Glyburide ..................................................................... 543 c. Glimepiride ................................................................... 543 d. Glipizide and gliclazide ......................................................... 544 3. Angiotensin II blockers............................................................ 544 a. Losartan ...................................................................... 544 b. Candesartan .................................................................. 544 c. Irbesartan .................................................................... 545 4. Nonsteroidal anti-inflammatory drugs .............................................. 545 a. Diclofenac..................................................................... 545 b. Ibuprofen ..................................................................... 545 c. Oxicams ...................................................................... 545 d. Celecoxib...................................................................... 545 e. Other selective cyclooxygenase-2 inhibitors ....................................... 546 f. Nonsteroidal anti-inflammatory drugs (in general) and clinical outcomes ............ 546 5. Phenytoin........................................................................ 546 6. Other drugs ...................................................................... 547 7. Summary of CYP2C9 ............................................................. 547 C. CYP2C19 ........................................................................... 548 1. Proton pump inhibitors............................................................ 548 2. Benzodiazepines .................................................................. 551 3. Tricyclic antidepressants .......................................................... 552 4. Selective serotonin reuptake inhibitors.............................................. 552 5. Barbiturates ..................................................................... 552 6. Proguanil ........................................................................ 553 7. Phenytoin........................................................................ 553 8. Moclobemide ..................................................................... 554 9. Other drugs ...................................................................... 554 10. Summary of CYP2C19 ............................................................ 554 D. Other cytochromes P450 ............................................................. 554 1. CYP2B6 ......................................................................... 554 a. Bupropion..................................................................... 555 b. Efavirenz ..................................................................... 555 2. CYP2C8 ......................................................................... 555 a. Paclitaxel ..................................................................... 556 b. Ibuprofen ..................................................................... 556 c. Repaglinide ................................................................... 556 d. Thiazolidinediones ............................................................. 557 e. Cerivastatin ................................................................... 557 f. Summary ..................................................................... 557 3. CYP3A5 ......................................................................... 557 a. Midazolam .................................................................... 558 PHARMACOGENETICS, DRUG