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Evaluation of 227 Drugs for In Vitro Inhibition of Cytochrome P450 2B6

From Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton/New London Laboratories, Groton, Connecticut.

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 µM. 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 µM, respectively). Other inhibitors (IC₅₀ < 1 µM) 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.

Key Words: Drug-drug interactions • HPLC/MS/MS • in vitro • P450 2B6 • rhCYP2B6

Address for reprints: Robert L. Walsky, MS 8118D-2010, Groton/New London Laboratories, Pfizer, Inc., Eastern Point Road, Groton, CT 06340; e-mail: robert.l.walsky{at}pfizer.com.

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