Robertson P, DeCory H H, Madan A, Parkinson A
Department of Drug Safety and Disposition, Cephalon, Inc., West Chester, Pennsylvania, USA.
Drug Metab Dispos. 2000 Jun;28(6):664-71.
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 microM) was evaluated with pooled human liver microsomes. Modafinil exhibited minimal capacity to inhibit any CYP enzyme, except CYP2C19. Modafinil inhibited the 4'-hydroxylation of S-mephenytoin, a marker substrate for CYP2C19, reversibly and competitively with a K(i) value of 39 microM, which approximates the steady-state C(max) 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 microM). 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 microM), 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.
在体外研究了莫达非尼对人肝细胞色素P450（CYP）活性的影响。用混合人肝微粒体评估了莫达非尼（5 - 250微摩尔）对CYP1A2、CYP2A6、CYP2B6、CYP2C9、CYP2C19、CYP2D6、CYP2E1、CYP3A4/5和CYP4A9/11的抑制潜力。莫达非尼除对CYP2C19外，对其他任何CYP酶的抑制能力均极小。莫达非尼可逆性且竞争性地抑制CYP2C19的标记底物S - 美芬妥因的4'-羟基化，其抑制常数（K(i)）值为39微摩尔，这接近莫达非尼在400毫克/天剂量下人体血浆中的稳态血药浓度峰值（C(max)）值。未观察到对任何CYP酶的不可逆抑制，也没有代谢依赖性抑制的证据。通过将人原代肝细胞培养物暴露于莫达非尼（10 - 300微摩尔）来评估其诱导CYP活性的潜力。然后制备微粒体并检测CYP1A2、CYP2A6、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6和CYP3A4/5的活性。来自经莫达非尼处理的肝细胞的微粒体CYP1A2、CYP2B6和CYP3A4/5的平均活性高于溶剂处理对照组（高达2倍），但低于这些酶的参考诱导剂所产生的活性。在高浓度莫达非尼（≥100微摩尔）下，CYP2C9的平均活性相对于溶剂对照组降低（高达60%）。总体而言，体外研究表明莫达非尼对人肝CYP1A2、CYP2B6、CYP2C9、CYP2C19和CYP3A4/5活性有影响。尽管体外获得的结果并不总是能预测体内的影响，但这些结果为理解临床观察到的药物相互作用以及规划后续研究提供了合理依据。
