Shimizu Maki, Fuse Kaori, Okudaira Kazuho, Nishigaki Ryuichiro, Maeda Kazuya, Kusuhara Hiroyuki, Sugiyama Yuichi
Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Drug Metab Dispos. 2005 Oct;33(10):1477-81. doi: 10.1124/dmd.105.004622. Epub 2005 Jul 13.
Fexofenadine hydrochloride (FEX), a second generation H(1)-receptor antagonist, is mainly eliminated from the liver into bile in unchanged form. Recent studies have shown that FEX can be accepted by human MDR1 (P-glycoprotein), OATP1A2 [organic anion-transporting polypeptide (OATP)-A, and OATP2B1 (OATP-B)] expression systems. However, other transporters responsible for the hepatic uptake of FEX have not yet been identified. In the present study, we evaluated the contribution of OATP family transporters, namely OATP1B1 (OATP2/OATP-C), OATP1B3 (OATP8), and OATP2B1 (OATP-B), to FEX uptake using transporter-expressing HEK293 (human embryonic kidney) cells. The uptake of FEX in OATP1B3-expressing cells was significantly greater than that in vector-transfected cells. On the other hand, OATP1B1- or OATP2B1-mediated uptake of FEX was not statistically significant. OATP1B3-mediated transport could be explained by a one-saturable component with a Michaelis constant (K(m)) of 108 +/- 11 microM. The inhibitory effect of FEX on the uptake of estrone-3-sulfate (E(1)S), cholecystokinin octapeptide (CCK-8), and 17beta-estradiol-17beta-d-glucuronide (E(2)17betaG) was also examined. Both OATP1B1- and OATP1B3-mediated E(2)17betaG uptake was inhibited by FEX. The K(i) values were 148 +/- 61 and 205 +/- 72 microM for OATP1B1 and OATP1B3, respectively. FEX also inhibited OATP1B3-mediated CCK-8 uptake and OATP1B1-mediated E(1)S uptake with a K(i) value of 83.3 +/- 15.3 and 257 +/- 84 microM, respectively, suggesting that FEX could not be used as a specific inhibitor for OATP1B1 and OATP1B3, although FEX was preferentially accepted by OATP1B3. In conclusion, this is, to our knowledge, the first demonstration that OATP1B3 is thought to be a major transporter involved in hepatic uptake of FEX in humans.
盐酸非索非那定（FEX）是一种第二代H(1)受体拮抗剂，主要以原形从肝脏排泄至胆汁中。最近的研究表明，FEX能够被人MDR1（P-糖蛋白）、OATP1A2[有机阴离子转运多肽（OATP）-A]和OATP2B1（OATP-B）表达系统所摄取。然而，其他负责FEX肝脏摄取的转运体尚未被鉴定出来。在本研究中，我们利用表达转运体的HEK293（人胚肾）细胞评估了OATP家族转运体，即OATP1B1（OATP2/OATP-C）、OATP1B3（OATP8）和OATP2B1（OATP-B）对FEX摄取的贡献。在表达OATP1B3的细胞中FEX的摄取显著高于载体转染细胞。另一方面，OATP1B1或OATP2B1介导的FEX摄取无统计学意义。OATP1B3介导的转运可用一个米氏常数（K(m)）为108±11μM的单饱和成分来解释。还研究了FEX对硫酸雌酮（E(1)S）、八肽胆囊收缩素（CCK-8）和17β-雌二醇-17β-D-葡萄糖醛酸苷（E(2)17βG）摄取的抑制作用。FEX抑制了OATP1B1和OATP1B3介导的E(2)17βG摄取。OATP1B1和OATP1B3的抑制常数（K(i)）值分别为148±61和205±72μM。FEX还抑制了OATP1B3介导的CCK-8摄取和OATP1B1介导的E(1)S摄取，其K(i)值分别为83.3±15.3和257±84μM，这表明尽管FEX优先被OATP1B3摄取，但它不能用作OATP1B1和OATP1B3的特异性抑制剂。总之，据我们所知，这是首次证明OATP1B3被认为是参与人体肝脏摄取FEX的主要转运体。
