Merck KGaA, Darmstadt, Germany (G.V.-N., H.S., F.L., C.L., A.M., P.S., D.P.); Merck Global Health Institute, Ares Trading S.A. (a subsidiary of Merck KGaA, Darmstadt, Germany), Eysins, Switzerland (N.A.); Medicines for Malaria Venture (MMV), Geneva, Switzerland (N.A.); and Certara UK Ltd (Simcyp Division), Sheffield, United Kingdom (H.B.).
Merck KGaA, Darmstadt, Germany (G.V.-N., H.S., F.L., C.L., A.M., P.S., D.P.); Merck Global Health Institute, Ares Trading S.A. (a subsidiary of Merck KGaA, Darmstadt, Germany), Eysins, Switzerland (N.A.); Medicines for Malaria Venture (MMV), Geneva, Switzerland (N.A.); and Certara UK Ltd (Simcyp Division), Sheffield, United Kingdom (H.B.)
Drug Metab Dispos. 2020 Jun;48(6):481-490. doi: 10.1124/dmd.119.089888. Epub 2020 Mar 19.
The active enantiomer R-Praziquantel (PZQ) shows a clinically lower relative exposure when administered enantiomerically pure compared with a racemic form. We investigated the hypothesis that enantiomer-enantiomer interactions on cytochrome P450 (P450) enzymes could explain this observation and aimed to further deepen the understanding of PZQ metabolism. First, in an in vitro metabolite profiling study, the formation of multiple metabolites per P450, together with an observed interconversion of cis-4'-OH-PZQ to trans-4'-OH-PZQ in human hepatocytes, pointed out the inadequacy of measuring metabolite formation in kinetic studies. Thus, a substrate depletion approach to study PZQ enantiomeric interactions was applied. Second, an abundant CYP3A4 metabolite found in previous studies was structurally characterized. Third, substrate depletion methodologies were applied to determine P450 enzyme kinetics of PZQ and to further estimate enantiomer-enantiomer inhibitory parameters. A competitive inhibition between PZQ enantiomers for CYP2C9, 2C19, 3A4, and 3A5 was revealed. Analyses considering the clearance of only one or both enantiomers provided comparable enantiomer-enantiomer inhibition estimates. To conclude, this paper provides new insights into PZQ metabolic profile to enable a better understanding of enantioselective pharmacokinetics using substrate depletion-based methods. SIGNIFICANCE STATEMENT: In this study, enantiomer-enantiomer interactions of praziquantel on cytochrome P450 metabolizing enzymes are investigated via substrate depletion measurement using modeling methods. Together with new insights into the praziquantel metabolism, this work provides a novel data set to understand its pharmacokinetics.
活性对映体 R-吡喹酮（PZQ）在与外消旋形式相比以纯对映体给药时显示出临床相对较低的相对暴露。我们假设细胞色素 P450（P450）酶上的对映体-对映体相互作用可以解释这一观察结果，并旨在进一步加深对 PZQ 代谢的理解。首先，在体外代谢物分析研究中，每一种 P450 形成多种代谢物，以及在人肝细胞中观察到顺式-4'-OH-PZQ 向反式-4'-OH-PZQ 的互变异构，表明在动力学研究中测量代谢物形成是不充分的。因此，应用了底物耗竭方法来研究 PZQ 对映体相互作用。其次，对先前研究中发现的一种丰富的 CYP3A4 代谢物进行了结构表征。第三，应用底物耗竭方法来确定 PZQ 的 P450 酶动力学，并进一步估计对映体-对映体抑制参数。揭示了 PZQ 对映体对 CYP2C9、2C19、3A4 和 3A5 的竞争性抑制。仅考虑一种或两种对映体清除的分析提供了可比的对映体-对映体抑制估计。总之，本文提供了关于 PZQ 代谢谱的新见解，以便使用基于底物耗竭的方法更好地理解手性药代动力学。意义陈述：在这项研究中，通过使用建模方法进行底物耗竭测量，研究了吡喹酮对细胞色素 P450 代谢酶的对映体-对映体相互作用。结合对吡喹酮代谢的新见解，这项工作提供了一个新的数据集来理解其药代动力学。
