Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Pharmacol Rev. 2011 Jun;63(2):390-410. doi: 10.1124/pr.110.002584. Epub 2011 Apr 13.
CYP3A is one of the most important drug-metabolizing enzymes, determining the first-pass metabolism, oral bioavailability, and elimination of many drugs. It is also an important determinant of variable drug exposure and is involved in many drug-drug interactions. Recent studies with CYP3A knockout and transgenic mice have yielded a number of key insights that are important to consider during drug discovery and development. For instance, studies with tissue-specific CYP3A-transgenic mice have highlighted the importance of intestinal CYP3A-dependent metabolism. They also revealed that intestinal CYP3A plays an important role in the regulation of various drug-handling systems in the liver. Intestinal CYP3A activity can thus have far-reaching pharmacological effects. Besides CYP3A, the active drug efflux transporter P-glycoprotein also has a strong effect on the pharmacokinetics of numerous drugs. CYP3A and P-glycoprotein have an extensive overlap in their substrate spectrum. It has been hypothesized that for many drugs, the combined activity of CYP3A and P-glycoprotein makes for efficient intestinal first-pass metabolism of orally administered drugs as a result of a potentially synergistic collaboration. However, there is only limited in vitro and in vivo evidence for this hypothesis. There has also been some confusion in the field about what synergy actually means in this case. Our recent studies with Cyp3a/P-glycoprotein combination knockout mice have provided further insights into the CYP3A-P-glycoprotein interplay. We here present our view of the status of the synergy hypothesis and an attempt to clarify the existing confusion about synergy. We hope that this will facilitate further critical testing of the hypothesis and improve communication among researchers. Above all, the recent findings and insights into the interplay between CYP3A and P-glycoprotein may have implications for improving oral drug bioavailability and reducing adverse side effects.
CYP3A 是最重要的药物代谢酶之一，决定了许多药物的首过代谢、口服生物利用度和消除。它也是药物暴露变异性的重要决定因素，并参与许多药物相互作用。最近使用 CYP3A 敲除和转基因小鼠的研究提供了许多关键见解，这些见解在药物发现和开发过程中非常重要。例如，使用组织特异性 CYP3A 转基因小鼠的研究强调了肠道 CYP3A 依赖性代谢的重要性。它们还揭示了肠道 CYP3A 在调节肝脏中各种药物处理系统方面发挥着重要作用。因此，肠道 CYP3A 活性可以产生深远的药理学影响。除了 CYP3A，活性药物外排转运蛋白 P-糖蛋白也对许多药物的药代动力学有很强的影响。CYP3A 和 P-糖蛋白在其底物谱上有广泛的重叠。有人假设，对于许多药物，CYP3A 和 P-糖蛋白的联合活性通过可能的协同合作，构成了口服给予药物的有效肠道首过代谢。然而，目前仅有有限的体外和体内证据支持这一假设。在该领域，对于协同作用实际上意味着什么，也存在一些混淆。我们最近使用 Cyp3a/P-糖蛋白组合敲除小鼠的研究进一步深入了解了 CYP3A-P-糖蛋白的相互作用。我们在这里提出了我们对协同作用假设的看法，并试图澄清关于协同作用的现有混淆。我们希望这将有助于进一步对该假设进行关键测试，并改善研究人员之间的沟通。最重要的是，CYP3A 和 P-糖蛋白之间相互作用的最新发现和见解可能对提高口服药物生物利用度和减少不良反应产生影响。
