Quantitative investigation of hepatobiliary transport of [11C] telmisartan in humans by PET imaging

被引:11
作者
Maeda, Kazuya [1 ]
Ohnishi, Akihito [2 ]
Sasaki, Masahiro [2 ]
Ikari, Yasuhiko [2 ]
Aita, Kazuki [2 ]
Watanabe, Yasuyoshi [3 ,4 ]
Kusuhara, Hiroyuki [1 ]
Sugiyama, Yuichi [5 ]
Senda, Michio [2 ]
机构
[1] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan
[2] Kobe City Med Ctr Gen Hosp, Div Mol Imaging, Inst Biomed Res & Innovat, Chuo Ku, 2-2 Minatojima Minamimachi, Kobe, Hyogo 6500047, Japan
[3] RIKEN Ctr Life Sci Technol, Chuo Ku, 6-7-3 Minatojima Minamimachi, Kobe, Hyogo 6500047, Japan
[4] Ctr Biosyst Dynam Res, Chuo Ku, 6-7-3 Minatojima Minamimachi, Kobe, Hyogo 6500047, Japan
[5] RIKEN, RIKEN Cluster Sci Technol & Innovat Hub, RIKEN Baton Zone Program, Sugiyama Lab,Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan
关键词
Telmisartan; Positron emission tomography (PET); Hepatobiliary transport; Integration plot; Nonlinear pharmacokinetics; POSITRON-EMISSION-TOMOGRAPHY; HEPATIC-UPTAKE; EFFLUX TRANSPORTERS; POLYPEPTIDE; OATP; PHARMACOKINETICS; EXCRETION; RATS;
D O I
10.1016/j.dmpk.2019.02.004
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The pharmacokinetics of telmisartan are nonlinear within the clinical dose range. To identify the underlying mechanism of this nonlinearity, we conducted a PET study in healthy subjects using [C-11]telmisartan. Eight healthy male subjects were enrolled in a 2-way crossover study. PET imaging was performed after intravenous administration of [C-11]telmisartan with or without a 1-h oral predose of two 40 mg Micardis (R) tablets. About 60% of the injected [C-11]telmisartan accumulated in the liver within 10 min after injection. With predosing of 80 mg telmisartan, the systemic elimination of [C-11] telmisartan was slightly delayed, but the liver exposure started to decrease earlier and biliary excretion was greatly enhanced. Hepatic uptake clearance of the radioactivity was not changed by telmisartan predosing, whereas the biliary clearance of radioactivity from the liver was significantly increased. Thus, the alteration in the pharmacokinetics of the radioactivity could not be explained simply by the saturation of hepatic uptake. Therefore, other mechanisms, such as the saturation of intracellular binding of telmisartan and/or its glucuronide, and the glucuronidation of telmisartan by uridine 5'-diphospho-glucuronosyltransferases, should be considered. This is the first reported human PET study using [C-11]telmisartan, the results of which can assist understanding of the hepatobiliary transport of telmisartan in humans. (C) 2019 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
引用
收藏
页码:293 / 299
页数:7
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