Department of Clinical Pharmacology, Center of Drug Absorption and Transport, University Medicine Greifswald, Greifswald, Germany.
Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Szczecin, Poland.
Basic Clin Pharmacol Toxicol. 2019 Mar;124(3):245-255. doi: 10.1111/bcpt.13137. Epub 2018 Oct 26.
The oral bioavailability of many drugs is highly influenced not only by hepatic but also by intestinal biotransformation. To estimate the impact of intestinal phase I and II metabolism on oral drug absorption, knowledge on the expression levels of the respective enzymes is an essential prerequisite. In addition, the potential interplay of metabolism and transport contributes to drug disposition. Both mechanisms may be subjected to coordinative regulation by nuclear receptors, leading to unwanted drug-drug interactions due to induction of intestinal metabolism and transport. Thus, it was the aim of this study to comprehensively analyse the regional expression of clinically relevant phase I and II enzymes along the entire human intestine and to correlate these data to expression data of drug transporters and nuclear receptors of pharmacokinetic relevance. Gene expression of 11 drug-metabolizing enzymes (CYP2B6, 2C8, 2C9, 2C19, 2D6, 3A4, 3A5, SULT1A, UGT1A, UGT2B7, UGT2B15) was studied in duodenum, jejunum, ileum and colon from six organ donors by real-time RT-PCR. Enzyme expression was correlated with expression data of the nuclear receptors PXR, CAR and FXR as well as drug transporters observed in the same cohort. Intestinal expression of all studied metabolizing enzymes was significantly higher in the small intestine compared to colonic tissue. CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, SULT1A, UGT1A and UGT2B7 expression increased from the duodenum to jejunum but was markedly lower in the ileum. In the small intestine, that is, the predominant site of drug absorption, the highest expression has been observed for CYP3A4, CYP2C9, SULT1A and UGT1A. In addition, significant correlations were found between several enzymes and PXR as well as ABC transporters in the small intestine. In conclusion, the observed substantial site-dependent intestinal expression of several enzymes may explain regional differences in intestinal drug absorption. The detected correlations between intestinal enzymes, transporters and nuclear receptors provide indirect evidence for their coordinative expression, regulation and function in the human small intestine.
许多药物的口服生物利用度不仅受到肝脏的影响，还受到肠道生物转化的影响。为了评估肠道 I 相和 II 相代谢对口服药物吸收的影响，了解相应酶的表达水平是一个必要的前提。此外，代谢和转运的潜在相互作用有助于药物处置。这两种机制都可能受到核受体的协调调节，导致由于诱导肠道代谢和转运而产生不必要的药物相互作用。因此，本研究的目的是全面分析整个人体肠道中临床相关的 I 相和 II 相酶的区域表达，并将这些数据与药代动力学相关的药物转运体和核受体的表达数据相关联。通过实时 RT-PCR 研究了 6 名器官供者的十二指肠、空肠、回肠和结肠中 11 种药物代谢酶（CYP2B6、2C8、2C9、2C19、2D6、3A4、3A5、SULT1A、UGT1A、UGT2B7、UGT2B15）的基因表达。将酶表达与同一队列中观察到的核受体 PXR、CAR 和 FXR 以及药物转运体的表达数据相关联。与结肠组织相比，所有研究的代谢酶在小肠中的表达均显著更高。CYP2B6、CYP2C9、CYP2C19、CYP2D6、CYP3A4/5、SULT1A、UGT1A 和 UGT2B7 的表达从十二指肠到空肠增加，但在回肠中明显降低。在小肠中，即药物吸收的主要部位，CYP3A4、CYP2C9、SULT1A 和 UGT1A 的表达最高。此外，在小肠中还发现了几种酶与 PXR 以及 ABC 转运体之间的显著相关性。总之，观察到的几种酶在肠道中的显著部位依赖性表达可能解释了肠道药物吸收的区域差异。在肠道酶、转运体和核受体之间检测到的相关性提供了它们在人体小肠中协调表达、调节和功能的间接证据。
