TY - JOUR T1 - In Vitro Inhibition and Induction of Human Hepatic Cytochrome P450 Enzymes by Modafinil JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 664 LP - 671 VL - 28 IS - 6 AU - Philmore Robertson AU - Heleen H. DeCory AU - Ajay Madan AU - Andrew Parkinson Y1 - 2000/06/01 UR - http://dmd.aspetjournals.org/content/28/6/664.abstract N2 - The ability of modafinil to affect human hepatic cytochrome P450 (CYP) activities was examined in vitro. The potential for inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 by modafinil (5–250 μM) was evaluated with pooled human liver microsomes. Modafinil exhibited minimal capacity to inhibit any CYP enzyme, except CYP2C19. Modafinil inhibited the 4′-hydroxylation ofS-mephenytoin, a marker substrate for CYP2C19, reversibly and competitively with a Ki value of 39 μM, which approximates the steady-stateCmax value of modafinil in human plasma at a dosage of 400 mg/day. No irreversible inhibition of any CYP enzyme was observed, and there was no evidence of metabolism-dependent inhibition. The potential for induction of CYP activity was evaluated by exposing primary cultures of human hepatocytes to modafinil (10–300 μM). Microsomes were then prepared and assayed for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 activities. The mean activities of microsomal CYP1A2, CYP2B6, and CYP3A4/5 from modafinil-treated hepatocytes were higher (up to 2-fold) than those in the solvent-treated controls but were less than those produced by reference inducers of these enzymes. At high concentrations of modafinil (≥100 μM), the mean activity of CYP2C9 was decreased (up to 60%) relative to that in the solvent controls. Overall, modafinil was shown to have effects on human hepatic CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5 activities in vitro. Although effects obtained in vitro are not always predictive of effects in vivo, such results provide a rational basis for understanding drug-drug interactions that are observed clinically and for planning subsequent investigations. The American Society for Pharmacology and Experimental Therapeutics ER -