Department of Chemistry, Kalamazoo College, Kalamazoo, Michigan.
Department of Chemistry, Kalamazoo College, Kalamazoo, Michigan
Drug Metab Dispos. 2019 Jun;47(6):567-573. doi: 10.1124/dmd.118.085928. Epub 2019 Apr 5.
Rolapitant [(Varubi), 5,8)-8-[[(1)-1-[3,5 bis(trifluoromethyl phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one] is a high-affinity NK1 receptor antagonist that was approved in September 2015 as a treatment for nausea and vomiting caused by chemotherapy. In vivo rolapitant moderately inhibits CYP2D6 for at least 7 days after one 180 mg dose. Due to the long inhibition time, we investigated rolapitant as a possible mechanism-based inactivator of CYP2D6. Rolapitant docked in the active site of CYP2D6 and displayed type I binding to CYP2D6 with a value of 1.2 ± 0.4 M. However, in NADPH-, time-, and concentration-dependent assays of CYP2D6 activity, no evidence for mechanism-based inactivation and no metabolites of rolapitant were observed. Stopped-flow binding studies yielded a / ( ) value of 6.2 M. The IC value for rolapitant inhibition of CYP2D6 activity was 24 M, suggesting that inhibition is not due to tight binding of rolapitant to CYP2D6. By Lineweaver-Burk analysis, rolapitant behaved as a mixed, reversible inhibitor. The values of 20 and 34 M were determined by Dixon analysis, with bufuralol and dextromethorphan as reporter substrates, respectively, and drug-drug interaction modeling did not predict the reported in vivo inhibition. The interaction of rolapitant with CYP2D6 was also examined in 1 microsecond molecular dynamics simulations. Rolapitant adopted multiple low-energy binding conformations near the active site, but at distances not consistent with metabolism. Given these findings, we do not see evidence that rolapitant is a mechanism-based inactivator. Moreover, the reversible inhibition of CYP2D6 by rolapitant may not fully account for the moderate inhibition described in vivo.
Rolapitant[(Varubi)，(5,8)-8-[[(1)-1-[3,5-双(三氟甲基)苯基]乙氧基]甲基]-8-苯基-1,7-二氮杂螺[4.5]癸烷-2-酮]是一种高亲和力 NK1 受体拮抗剂，于 2015 年 9 月获批用于治疗化疗引起的恶心和呕吐。在单次给予 180mg 剂量后，体内 rolapitant 至少可在 7 天内中度抑制 CYP2D6。由于抑制时间较长，我们研究了 rolapitant 是否可能是 CYP2D6 的一种基于机制的失活剂。Rolapitant 与 CYP2D6 的活性位点对接，并与 CYP2D6 呈 I 型结合， 值为 1.2±0.4M。然而，在 NADPH、时间和浓度依赖性 CYP2D6 活性测定中，未观察到基于机制的失活作用，也未观察到 rolapitant 的代谢产物。停流结合研究得出 / ( )值为 6.2M。 rolapitant 抑制 CYP2D6 活性的 IC 值为 24M，提示抑制不是由于 rolapitant 与 CYP2D6 的紧密结合所致。通过 Lineweaver-Burk 分析，rolapitant 表现为混合、可逆抑制剂。通过 Dixon 分析确定 20 和 34M 的 值，分别以 bufuralol 和右美沙芬为报告底物，药物相互作用模型预测不出报告的体内抑制作用。还在 1 微秒分子动力学模拟中研究了 rolapitant 与 CYP2D6 的相互作用。 Rolapitant 在活性位点附近采用了多种低能量结合构象，但距离与代谢不一致。鉴于这些发现，我们没有看到 rolapitant 是一种基于机制的失活剂的证据。此外，rolapitant 对 CYP2D6 的可逆抑制作用可能无法完全解释体内描述的中度抑制作用。
