Dehydroepiandrosterone sulfate, a useful endogenous probe for evaluation of drug-drug interaction on hepatic organic anion transporting polypeptide (OATP) in cynomolgus monkeys
Dehydroepiandrosterone sulfate, a useful endogenous probe for evaluation of drug-drug interaction on hepatic organic anion transporting polypeptide (OATP) in cynomolgus monkeys
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DOI：
10.1016/j.dmpk.2014.12.009
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发表时间：
2015-04-01
影响因子：
2.1
通讯作者：
Tamai, Ikumi
中科院分区：
文献类型：
--
作者：
Watanabe, Masaki;Watanabe, Takao;Tamai, Ikumi
由于药物相互作用（DDI）可影响有机阴离子转运多肽（OATP）并导致临床事件，因此预测此类DDI在早期临床开发中非常重要。虽然他汀类药物是OATP介导的DDI的有用探针，但内源性探针对于预测此类DDI更实用。在这项研究中，我们研究了可能使用的硫酸脱氢表雄酮（DHEAS），内源性OATP底物，在预测OATP介导的DDI在食蟹猴作为第一步，在人类评估。在体外实验中，人和食蟹猴肝细胞均显示出时间和温度依赖性DHEAS摄取。利福平（RIF），一种典型的OATP抑制剂，抑制这种摄取，表明OATP参与DHEAS摄取。在体内实验中，给予RIF 10 mg/kg后，DHEAS的血浆浓度-时间曲线下面积（AUC）和最大血浆浓度（C-max）显著增加，尽管这种增加的程度低于本研究中使用的试验他汀类药物观察到的增加程度。然而，基于体外肝脏DHEAS摄取的结果，预计DHEAS浓度的变化在人中比在猴中更显著。这首次表明DHEAS可作为预测OATP介导的DDI的内源性探针。Copyright（C）2015，The Japanese Society for the Study of Xenobiotics.由爱思唯尔有限公司出版。保留所有权利。
Since drug-drug interaction (DDI) can affect organic anion-transporting polypeptide (OATP) and cause clinical events, prediction of such DDI is important in early clinical development. Although statins are useful probes for OATP-mediated DDI, endogenous probes would be more practical for predicting such DDI. In this study, we investigate the possible use of dehydroepiandrosterone sulfate (DHEAS), an endogenous OATP substrate, in predicting OATP-mediated DDI in cynomolgus monkeys as a first step toward in human assessment. In in vitro experiments, both human and cynomolgus monkey hepatocytes showed a time-and temperature-dependent DHEAS uptake. Rifampicin (RIF), a typical OATP inhibitor, inhibited this uptake, indicating the involvement of OATP in DHEAS uptake. In in vivo experiments, the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C-max) of DHEAS were significantly increased following administration of RIF 10 mg/kg, although the extent of this increase was lower than that observed with the test-statins used in this study. However, based on the results of in vitro hepatic DHEAS uptake, changes in DHEAS concentration are expected to be more prominent in human than in monkey. This shows for the first time that DHEAS may be used as endogenous probe for predicting OATP-mediated DDI. Copyright (C) 2015, The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.