Investigation of the Role of Transporters on the Hepatic Elimination of an LAT1 Selective Inhibitor JPH203
Investigation of the Role of Transporters on the Hepatic Elimination of an LAT1 Selective Inhibitor JPH203
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DOI：
10.1002/jps.23601
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发表时间：
2013-09-01
影响因子：
3.8
通讯作者：
Sugiyama, Yuichi
中科院分区：
文献类型：
--
作者：
Toyoshima, Junko;Kusuhara, Hiroyuki;Sugiyama, Yuichi
JPH 203已被开发为抑制L型氨基酸转运蛋白1介导的必需氨基酸摄取到肿瘤细胞中的抗癌药物。本研究旨在阐明哪些药物转运蛋白可能参与JPH 203的肝脏消除，并估计人体肝脏清除率。在Sprague-Dawley大鼠中，JPH 203的全身清除率接近血流速度。通过II期代谢的JPH 203生物转化产生N-乙酰基-JPH 203（NAc-JPH 203）。NAc-JPH 203在胆汁中积累，并且NAc-JPH 203小管流出在Mrp 2缺陷型突变大鼠（Mrp 2高胆红素血症大鼠）中显著减少。JPH 203和NAc-JPH 203是有机阴离子转运蛋白[有机阴离子转运多肽（OATP）1B 1、OATP 1B 3、OATP 2B 1和OAT 3]底物。在人冻存肝细胞中，JPH 203摄取是饱和的，并被利福平（一种原型OATP抑制剂）抑制。JPH 203代谢清除率大于流入清除率和最终被动清除率; JPH 203摄取似乎是总体肝脏消除的速率决定过程。此外，与大鼠不同，预测人肝脏清除率为固有清除率限制。这些结果表明，肝摄取转运蛋白是决定JPH 203全身暴露的决定性因素。(C)2013 Wiley Periodicals，Inc.
JPH203 has been developed as an anticancer drug that inhibits L-type amino acid transporter 1-mediated essential amino acid uptake into tumor cells. This study sought to elucidate which drug transporters may be involved in JPH203 hepatic elimination, and to estimate human hepatic clearance. In Sprague-Dawley rats, JPH203 total body clearance approached blood flow rate. JPH203 biotransformation via phase II metabolism produces N-acetyl-JPH203 (NAc-JPH203). NAc-JPH203 accumulates in the bile, and NAc-JPH203 canalicular efflux was significantly decreased in Mrp2-deficient mutant rats (Eisai hyperbilirubinemic rats). JPH203 and NAc-JPH203 are organic anion transporters [ organic anion transporting polypeptide (OATP)1B1, OATP1B3, OATP2B1, and OAT3] substrates. In human cryopreserved hepatocytes, JPH203 uptake was saturable and inhibited by rifampicin, a prototypical OATP inhibitor. JPH203 metabolic clearance was larger than influx clearance and eventually passive clearance; JPH203 uptake appears to be the rate-determining process in overall hepatic elimination. Furthermore, unlike rats, the human hepatic clearance was predicted to be intrinsic clearance rate limited. These results suggest that the hepatic uptake transporters are determinant factors to determine JPH203 systemic exposure. (C) 2013 Wiley Periodicals, Inc.