Regional Difference in the Effect of Influx/Efflux Transporters and Metabolic Enzymes on Intestinal Drug Absorption

在本研究中，我们旨在阐明转运蛋白和代谢酶在肠道药物吸收中的位置特异性贡献。大鼠对他林洛尔和秋水仙碱的原位研究表明，部位特异性药物吸收可能是由于OATP和P-gp的不同表达和功能所致。进一步分析表明，OATP2B1上存在多个与药物亲和力不同的结合部位。同时，微粒体研究表明，CYP3A5基因和表达水平对药物代谢的抑制作用有显著影响，但其影响的大小是抑制物-底物对的。这项针对CYP2C19的研究结果表明，尽管代谢物对体内DDiS有贡献，但它们在循环中的相对丰度并不能预测它们对体内DDI风险的贡献。这些发现揭示了流入/流出转运体和代谢酶参与了肠道药物吸收过程。

In the present study, we aimed to clarify the site-specific contribution of transporters and metabolic enzymes to the intestinal drug absorption. The rat in situ studies with talinolol and colchicine demonstrated site-specific drug absorption presumably due to differential expression and function of OATP and P-gp. Further analysis revealed presence of multiple binding sites on OATP2B1 with different affinity for drugs. Meanwhile, microsomal studies demonstrated that CYP3A5 genotype and expression level have a significant impact on inhibitory potency for CYP3A-catalyzed drug metabolism, but that the magnitude of its effect is inhibitor-substrate pair specific. The results of the study focusing on CYP2C19 show that, although metabolites contribute to in vivo DDIs, their relative abundance in circulation does not predict their contribution to in vivo DDI risk. These findings revealed involvement of influx/efflux transporters and metabolic enzymes in the intestinal drug absorption process.