Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas 77030, USA.
J Pharm Sci. 2012 Jan;101(1):381-93. doi: 10.1002/jps.22738. Epub 2011 Sep 8.
Understanding of the interdependence of cytochrome P450 enzymes and P-glycoprotein in disposition of drugs (also termed "transport-metabolism interplay") has been significantly advanced in recent years. However, whether such "interplay" exists between phase II metabolic enzymes and efflux transporters remains largely unknown. The objective of this article is to explore the role of efflux transporters (acting on the phase II metabolites) in disposition of the parent drug in Caco-2 cells, liver, and intestine via simulations utilizing a catenary model (for Caco-2 system) and physiologically based pharmacokinetic (PBPK) models (for the liver and intestine). In all three models, "transport-metabolism interplay" (i.e., inhibition of metabolite efflux decreases the metabolism) can be observed only when futile recycling (or deconjugation) occurred. Futile recycling appeared to bridge the two processes (i.e., metabolite formation and excretion) and enable the interplay thereof. Without futile recycling, metabolite formation was independent on its downstream process excretion, thus impact of metabolite excretion on its formation was impossible. Moreover, in liver PBPK model with futile recycling, impact of biliary metabolite excretion on the exposure of parent drug [(systemic (reservoir) area under the concentration-time curve (AUC(R1))] was limited; a complete inhibition of efflux resulted in AUC(R1) increases of less than 1-fold only. In intestine PBPK model with futile recycling, even though a complete inhibition of efflux could result in large elevations (e.g., 3.5-6.0-fold) in AUC(R1), an incomplete inhibition of efflux (e.g., with a residual activity of ≥ 20% metabolic clearance) saw negligible increases (<0.9-fold) in AUC(R1). In conclusion, this study presented mechanistic observations of pharmacokinetic interplay between phase II enzymes and efflux transporters. Those studying such "interplay" are encouraged to adequately consider potential consequences of inhibition of efflux transporters in humans.
近年来，人们对细胞色素 P450 酶和 P-糖蛋白在药物处置中的相互依存关系（也称为“转运-代谢相互作用”）有了更深入的了解。然而，关于 II 相代谢酶和外排转运体之间是否存在这种“相互作用”，目前仍知之甚少。本文的目的是通过利用级联模型（用于 Caco-2 系统）和基于生理学的药代动力学（PBPK）模型（用于肝脏和肠道）进行模拟，探讨外排转运体（作用于 II 相代谢物）在 Caco-2 细胞、肝脏和肠道中对母体药物处置的作用。在所有三种模型中，只有当无效循环（或去共轭）发生时，才能观察到“转运-代谢相互作用”（即，代谢物外排的抑制降低了代谢）。无效循环似乎连接了两个过程（即代谢物的形成和排泄），并使它们相互作用。如果没有无效循环，代谢物的形成就独立于其下游排泄过程，因此代谢物排泄对其形成的影响是不可能的。此外，在具有无效循环的肝脏 PBPK 模型中，胆汁代谢物排泄对母体药物暴露的影响[系统（储库）浓度-时间曲线下面积（AUC（R1））]是有限的；只有完全抑制外排才能使 AUC（R1）增加不到 1 倍。在具有无效循环的肠道 PBPK 模型中，即使完全抑制外排可使 AUC（R1）升高 3.5-6.0 倍，但不完全抑制外排（例如，残留的外排清除率≥20%）则可使 AUC（R1）仅增加不到 0.9 倍。总之，本研究提出了 II 相酶和外排转运体之间药代动力学相互作用的机制观察。那些研究这种“相互作用”的人应充分考虑抑制外排转运体在人体内可能产生的后果。
