期刊
DRUG METABOLISM AND DISPOSITION
卷 37, 期 3, 页码 447-452出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/dmd.108.023465
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资金
- National Institutes of Health National Institute of General Medical Sciences [GM 41935]
Previous reports have indicated that in vitro biliary clearance (CIbiliary) determined in sandwich-cultured hepatocytes correlates well with in vivo CIbiliary for limited sets of compounds. The purpose of this study was 1) to determine the in vitro Clbiliary in sandwich-cultured human hepatocytes of angiotensin II receptor blockers and HMG-CoA reductase inhibitors that undergo limited metabolism and 2) to compare the predicted CIbiliary values with estimated in vivo hepatic clearance data in humans. The average biliary excretion index and in vitro intrinsic CIbiliary values of olmesartan, valsartan, pravastatin, rosuvastatin, and pitavastatin in sandwich-cultured human hepatocytes were 35, 23, 31, 25, and 16%, respectively, and 0.943, 1.20, 0.484, 3.39, and 5.48 ml/min/kg, respectively. CIbiliary values predicted from sandwich-cultured human hepatocytes correlated with estimated in vivo hepatic clearance values based on published data (no in vivo data in humans was available for pitavastatin), and the rank order was also consistent. In conclusion, in vitro CIbiliary determined in sandwich-cultured human hepatocytes can be used to predict in vivo CIbiliary of compounds in humans.
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