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

在本研究中，我们的目的是澄清转运蛋白和代谢酶对肠道药物吸收的位点特异性贡献。他林洛尔和秋水仙碱的大鼠原位研究表明，可能由于OATP和P-gp的差异表达和功能，药物吸收具有位点特异性。进一步分析显示OATP 2B 1上存在多个结合位点，对药物具有不同的亲和力。同时，微粒体研究表明，CYP 3A 5基因型和表达水平对CYP 3A催化的药物代谢的抑制效力有显著影响，但其影响程度具有底物-底物对特异性。关注CYP 2C 19的研究结果表明，尽管代谢物有助于体内DDI，但其在循环中的相对丰度并不能预测其对体内DDI风险的贡献。这些发现揭示了内流/外排转运蛋白和代谢酶参与肠道药物吸收过程。

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.