Michiba Kazuyoshi, Maeda Kazuya, Kurimori Ko, Enomoto Tsuyoshi, Shimomura Osamu, Takeuchi Tomoyo, Nishiyama Hiroyuki, Oda Tatsuya, Kusuhara Hiroyuki
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.Mi., K.Ma., H.K.); Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan (K.K., T.E., O.S., T.O.); and Tsukuba Human Tissue Biobank Center, University of Tsukuba Hospital, Ibaraki, Japan (T.T., H.N.).
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.Mi., K.Ma., H.K.); Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan (K.K., T.E., O.S., T.O.); and Tsukuba Human Tissue Biobank Center, University of Tsukuba Hospital, Ibaraki, Japan (T.T., H.N.)
Drug Metab Dispos. 2021 Jan;49(1):84-93. doi: 10.1124/dmd.120.000138. Epub 2020 Oct 21.
Intestinal permeability is a critical factor for orally administered drugs. It can be facilitated by uptake transporters or limited by efflux transporters and metabolic enzymes in the intestine. The present study aimed to characterize the Ussing chamber system incorporating human intestinal tissue as an in vitro model for investigating the impact of intestinal uptake/efflux transporters on the intestinal absorption of substrate drugs in humans. We confirmed the functions of major intestinal uptake/efflux drug transporters in freshly isolated human jejunum sections by demonstrating a significant decrease in the mucosal uptake of cefadroxil (peptide transporter 1) and methotrexate (proton-coupled folate transporter), mucosal-to-serosal permeability of ribavirin (concentrative nucleoside transporters/equilibrative nucleoside transporters), and serosal-to-mucosal permeability of P-glycoprotein and breast cancer resistance protein substrates in the presence of their typical inhibitors. The mucosal-to-serosal apparent permeability coefficients (P) of 19 drugs, including substrates of drug transporters and cytochrome P450 3A, ranged from 0.60 × 10 to 29 × 10 cm/s and showed a good correlation with reported fraction of an oral dose that enters the gut wall and passes into the portal circulation with escaping intestinal metabolism (FaFg) values in humans. Furthermore, the P values for cefadroxil, methotrexate, and ribavirin in the presence of the corresponding transporter inhibitors underestimated the FaFg of these drugs, which clearly showed that intestinal uptake transporters facilitate their intestinal absorption in humans. In conclusion, the functions of major intestinal uptake/efflux drug transporters could be maintained in freshly isolated human jejunum sections. The Ussing chamber system incorporating human intestinal tissue would be useful for evaluating the impact of intestinal uptake/efflux transporters on the intestinal absorption of various types of drugs in humans. SIGNIFICANCE STATEMENT: Although previous studies have predicted the intestinal absorption of drugs in humans using the Ussing chamber system incorporating human intestinal tissue, there is little systematic information about drug transport mediated by multiple transporters in this system. We confirmed the functions of major intestinal uptake/efflux transporters in freshly isolated human jejunum sections and demonstrated that the mucosal-to-serosal apparent permeability coefficient of various types of drugs showed a good correlation with reported human FaFg values.
肠道通透性是口服药物的一个关键因素。它可通过摄取转运体促进，也可受肠道中的外排转运体和代谢酶限制。本研究旨在将包含人肠道组织的尤斯灌流小室系统表征为一种体外模型，用于研究肠道摄取/外排转运体对人底物药物肠道吸收的影响。我们通过证明头孢羟氨苄（肽转运体1）和甲氨蝶呤（质子偶联叶酸转运体）的黏膜摄取显著降低、利巴韦林（集中性核苷转运体/平衡型核苷转运体）的黏膜到浆膜通透性以及P-糖蛋白和乳腺癌耐药蛋白底物在其典型抑制剂存在下的浆膜到黏膜通透性，证实了新鲜分离的人空肠段中主要肠道摄取/外排药物转运体的功能。19种药物（包括药物转运体和细胞色素P450 3A的底物）的黏膜到浆膜表观渗透系数（P）范围为0.60×10至29×10 cm/s，并且与报道的口服剂量进入肠壁并进入门静脉循环且逃避肠道代谢的分数（FaFg）值在人体中显示出良好的相关性。此外，在相应转运体抑制剂存在下头孢羟氨苄、甲氨蝶呤和利巴韦林的P值低估了这些药物的FaFg，这清楚地表明肠道摄取转运体促进了它们在人体中的肠道吸收。总之，主要肠道摄取/外排药物转运体的功能可在新鲜分离的人空肠段中得以维持。包含人肠道组织的尤斯灌流小室系统将有助于评估肠道摄取/外排转运体对人各种类型药物肠道吸收的影响。意义声明：尽管先前的研究使用包含人肠道组织的尤斯灌流小室系统预测了人体中的药物肠道吸收，但关于该系统中多种转运体介导的药物转运几乎没有系统的信息。我们证实了新鲜分离的人空肠段中主要肠道摄取/外排转运体的功能，并证明了各种类型药物的黏膜到浆膜表观渗透系数与报道的人体FaFg值显示出良好的相关性。
