期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 105, 期 2, 页码 854-863出版社
WILEY
DOI: 10.1002/jps.24564
关键词
in vitro/in vivo correlations (IVIVC); hepatic transport; hepatic metabolism; hepatic clearance; hepatocytes; HIV/AIDS; membrane transport; metabolism; organic anion-transporting polypeptide; transporters
资金
- Agency for Innovation by Science and Technology, Flanders
- Fonds voor Wetenschappelijk Onderzoek, Flanders
- Onderzoeksfonds of the KU Leuven, Belgium
The aim of this work was to explore the contribution of the organic anion transporting polypeptide-1B (OATP1B) drug transporters in the hepatic clearance (Cl) of all marketed HIV protease inhibitors (PI) in humans. HIV PI uptake rates in OATP1B1/1B3-transfected Chinese hamster ovary cells were converted to uptake Cl values in human hepatocytes via a relative activity factor, which was determined by comparing uptake of known substrates between OATP1B1/3-transfected cells and human hepatocytes. Metabolic Cl values were determined in human liver microsomes. In vivo hepatic Cl values were calculated either by combining drug uptake and metabolism or based on one of these individual Cl processes and compared with published in vivo hepatic Cl values. Excellent in vitro-in vivo correlation (R-2 = 0.85) was observed when only uptake Cl values were used, but not when only metabolic Cl was used (R-2 = 0.40). The correlation did not improve when both processes were taken into account (R-2 = 0.85). PBPK models confirmed the remarkable sensitivity of predicted exposure to hepatic drug uptake, indicating a key role for OATP1B1/3 in hepatic disposition of several HIV PI in man. This may contribute to the interindividual variability in systemic and hepatic exposure to these drugs in the clinic. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据