Li Ming, de Graaf Inge A M, van de Steeg Evita, de Jager Marina H, Groothuis Geny M M
Pharmacokinetics, Toxicology & Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
TNO (Netherlands Organization for Applied Scientific Research), Utrechtseweg 48, 3700 AJ Zeist, The Netherlands.
Toxicol In Vitro. 2017 Apr;40:26-33. doi: 10.1016/j.tiv.2016.12.002. Epub 2016 Dec 7.
Intestinal P-gp and CYP3A4 work coordinately to reduce the intracellular concentration of drugs, and drug-drug interactions (DDIs) based on this interplay are of clinical importance and require pre-clinical investigation. Using precision-cut intestinal slices (PCIS) of human jejunum, ileum and colon, we investigated the P-gp/CYP3A4 interplay and related DDIs with P-gp inhibitors at the different regions of the human intestine with quinidine (Qi), dual substrate of P-gp and CYP3A4, as probe. All the P-gp inhibitors increased the intracellular concentrations of Qi by 2.1-2.6 fold in jejunum, 2.6-3.8 fold in ileum but only 1.2-1.3 fold in colon, in line with the different P-gp expression in these intestinal regions. The selective P-gp inhibitors (CP100356 and PSC833) enhanced 3-hydroxy-quinidine (3OH-Qi) in jejunum and ileum, while dual inhibitors of P-gp and CYP3A4 (verapamil and ketoconazole) decreased the 3OH-Qi production, despite of the increased intracellular Qi concentration, due to inhibition of CYP3A4. The outcome of DDIs based on P-gp/CYP3A4 interplay, shown as remarkable changes in the intracellular concentration of both the parent drug and the metabolite, varied among the intestinal regions, probably due to the different expression of P-gp and CYP3A4, and were different from those found in rat PCIS, which may have important implications for the disposition and toxicity of drugs and their metabolites.
肠道P-糖蛋白（P-gp）和细胞色素P450 3A4（CYP3A4）协同作用以降低药物的细胞内浓度，基于这种相互作用的药物-药物相互作用（DDIs）具有临床重要性，需要进行临床前研究。我们使用人空肠、回肠和结肠的精密切割肠片（PCIS），以P-gp和CYP3A4的双重底物奎尼丁（Qi）作为探针，研究了人肠道不同区域的P-gp/CYP3A4相互作用以及与P-gp抑制剂相关的DDIs。所有P-gp抑制剂均可使空肠中Qi的细胞内浓度增加2.1至2.6倍，回肠中增加2.6至3.8倍，但结肠中仅增加1.2至1.3倍，这与这些肠道区域中不同的P-gp表达情况一致。选择性P-gp抑制剂（CP100356和PSC833）可提高空肠和回肠中3-羟基奎尼丁（3OH-Qi）的水平，而P-gp和CYP3A4的双重抑制剂（维拉帕米和酮康唑）尽管细胞内Qi浓度升高，但由于抑制了CYP3A4，导致3OH-Qi生成减少。基于P-gp/CYP3A4相互作用的DDIs结果表现为母体药物和代谢物细胞内浓度的显著变化，在不同肠道区域有所不同，这可能是由于P-gp和CYP3A4的表达不同所致，并且与大鼠PCIS中的结果不同，这可能对药物及其代谢物的处置和毒性具有重要意义。
