title: Evaluation of 227 drugs for in vitro inhibition of cytochrome P450 2B6.
abstract: Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of drugs such as bupropion, efavirenz, propofol, and selegiline, among others. More than 200 commonly prescribed drugs and other xenobiotics were examined for their ability to inhibit CYP2B6-mediated bupropion hydroxylase activity. Thirty compounds were found exhibiting greater than 50% inhibition at 30 microM. Inhibitors of CYP2B6 were identified from a wide variety of therapeutic classes. The 2 platelet aggregation inhibitors, clopidogrel and ticlopidine, were both identified as potent inhibitors (IC50 = 0.0206 and 0.149 microM, respectively). Other inhibitors (IC50 < 1 microM) included clotrimazole, itraconazole, sertraline, and raloxifene. These in vitro data were used along with clinical pharmacokinetic information in the prediction of potential drug-drug interactions that could occur by inhibition of CYP2B6. Although few drugs tested are expected to cause drug interactions, clopidogrel and ticlopidine were identified as being of concern as potential inhibitors of clinical relevance. These findings are discussed in context to potential drug interactions that could be observed between these agents and drugs for which CYP2B6 is involved in metabolism.
authors.affiliation: Pfizer Global Research and Development, Groton/New London Laboratories, Eastern Point Road, Groton, CT 06340, USA. robert.l.walsky@pfizer.com
authors.forename: Robert L
authors.initials: RL
authors.lastname: Walsky
authors.forename: Angela V
authors.initials: AV
authors.lastname: Astuccio
authors.forename: R Scott
authors.initials: RS
authors.lastname: Obach
mesh_terms: D000465:Algorithms; D000480:Alkynes; D018687:Antidepressive Agents, Second-Generation / Q000378:metabolism / Q000494:pharmacology; D000935:Antifungal Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019540:Area Under Curve; D048588:Benzoxazines; D016642:Bupropion / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000077144:Clopidogrel; D003022:Clotrimazole / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D017964:Itraconazole / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010078:Oxazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020849:Raloxifene Hydrochloride / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020280:Sertraline / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015262:Xenobiotics / Q000145:classification / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000480:Alkynes; D018687:Antidepressive Agents, Second-Generation; D000935:Antifungal Agents; D048588:Benzoxazines; D016642:Bupropion; D000077144:Clopidogrel; D003022:Clotrimazole; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D017964:Itraconazole; D010078:Oxazines; D010975:Platelet Aggregation Inhibitors; D020849:Raloxifene Hydrochloride; D018894:Reverse Transcriptase Inhibitors; D020845:Selective Estrogen Receptor Modulators; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; D013988:Ticlopidine; D015262:Xenobiotics; C585599:CYP2B6 protein, human; C098320:efavirenz; C496215:radafaxine