Darnaud Léa, Delage Clément, Daali Youssef, Trouvin Anne-Priscille, Perrot Serge, Khoudour Nihel, Merise Nadia, Labat Laurence, Etain Bruno, Bellivier Frank, Lloret-Linares Célia, Bloch Vanessa, Curis Emmanuel, Declèves Xavier
Biologie du Médicament-Toxicologie, AP-HP, Hôpital Cochin, 27 rue du Faubourg St. Jacques, 75679 Paris, France.
Faculty of Health, Université Paris Cité, Inserm, UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006 Paris, France.
Pharmaceutics. 2023 Mar 18;15(3):979. doi: 10.3390/pharmaceutics15030979.
Drug-metabolizing enzymes and drug transporters are key determinants of drug pharmacokinetics and response. The cocktail-based cytochrome P450 (CYP) and drug transporter phenotyping approach consists in the administration of multiple CYP or transporter-specific probe drugs to determine their activities simultaneously. Several drug cocktails have been developed over the past two decades in order to assess CYP450 activity in human subjects. However, phenotyping indices were mostly established for healthy volunteers. In this study, we first performed a literature review of 27 clinical pharmacokinetic studies using drug phenotypic cocktails in order to determine 95%,95% tolerance intervals of phenotyping indices in healthy volunteers. Then, we applied these phenotypic indices to 46 phenotypic assessments processed in patients having therapeutic issues when treated with painkillers or psychotropic drugs. Patients were given the complete phenotypic cocktail in order to explore the phenotypic activity of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A, and P-glycoprotein (P-gp). P-gp activity was evaluated by determining AUC for plasma concentrations over time of fexofenadine, a well-known substrate of P-gp. CYP metabolic activities were assessed by measuring the CYP-specific metabolite/parent drug probe plasma concentrations, yielding single-point metabolic ratios at 2 h, 3 h, and 6 h or AUC ratio after oral administration of the cocktail. The amplitude of phenotyping indices observed in our patients was much wider than those observed in the literature for healthy volunteers. Our study helps define the range of phenotyping indices with "normal" activities in human volunteers and allows classification of patients for further clinical studies regarding CYP and P-gp activities.
药物代谢酶和药物转运体是药物药代动力学和反应的关键决定因素。基于鸡尾酒法的细胞色素P450（CYP）和药物转运体表型分析方法是给予多种CYP或转运体特异性探针药物以同时测定它们的活性。在过去二十年中已开发出几种药物鸡尾酒用于评估人类受试者的CYP450活性。然而，表型分析指标大多是针对健康志愿者建立的。在本研究中，我们首先对27项使用药物表型鸡尾酒的临床药代动力学研究进行了文献综述，以确定健康志愿者表型分析指标的95%、95%耐受区间。然后，我们将这些表型指标应用于46例在使用止痛药或精神药物治疗时有治疗问题的患者所进行的表型评估。给予患者完整的表型鸡尾酒以探究CYP1A2、CYP2B6、CYP2C9、CYP2C19、CYP2D6、CYP3A和P-糖蛋白（P-gp）的表型活性。通过测定非索非那定（一种知名的P-gp底物）血浆浓度随时间的AUC来评估P-gp活性。通过测量CYP特异性代谢物/母体药物探针的血浆浓度来评估CYP代谢活性，在口服鸡尾酒2小时、3小时和6小时时得出单点代谢率或AUC比值。我们在患者中观察到的表型分析指标幅度比文献中在健康志愿者中观察到的要宽得多。我们的研究有助于确定人类志愿者中具有“正常”活性的表型分析指标范围，并允许对患者进行分类，以便进一步开展关于CYP和P-gp活性的临床研究。
