@article {Robertson664, author = {Philmore Robertson and Heleen H. DeCory and Ajay Madan and Andrew Parkinson}, title = {In Vitro Inhibition and Induction of Human Hepatic Cytochrome P450 Enzymes by Modafinil}, volume = {28}, number = {6}, pages = {664--671}, year = {2000}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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{\textendash}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{\textendash}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}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/28/6/664}, eprint = {https://dmd.aspetjournals.org/content/28/6/664.full.pdf}, journal = {Drug Metabolism and Disposition} }