Abstract
It has been reported that in vivo biliary clearance can be predicted using sandwich-cultured rat and human hepatocytes. The predicted apparent biliary clearance (CLbile, app) from sandwich- cultured rat hepatocytes (SCRH) based on medium concentrations correlates to in vivo CLbile, app based on plasma concentrations of angiotensin II receptor blockers (ARBs), HMG-CoA reductase inhibitors (statins), β-lactam antibiotics, and topotecan. However, the predicted biliary clearance from SCRH was 7- to 300-fold lower than in vivo biliary clearance. We speculated that the process of biliary excretion might not have been evaluated using sandwich-cultured hepatocytes. To evaluate this issue, intrinsic biliary clearance (CLbile, int) based on intracellular compound concentrations was evaluated to investigate the in vitro-in vivo correlation of this process among ARBs, statins, β-lactam antibiotics, and topotecan. Intrinsic biliary clearance in SCRH correlated to in vivo values obtained by constant intravenous infusion of six compounds, but not rosuvastatin and cefmetazole, to rats. Moreover, differences between SCRH and in vivo CLbile, int (0.7–6-fold) were much smaller than those of CLbile, app (7–300-fold). Therefore, in vivo CLbile, int is more accurately reflected using SCRH than CLbile, app. In conclusion, to predict in vivo biliary clearance more accurately, CLbile, int should be evaluated instead of CLbile, app between SCRH and in vivo.
Footnotes
This work was supported in part by the Japan Health Science Foundation [Grant “Research on Publicly Essential Drugs and Medical Devices”].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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ABBREVIATIONS:
- Oatp
- organic anion-transporting polypeptide
- Mdr
- multidrug resistance
- Mrp
- multidrug resistance-associated protein
- Bcrp
- breast cancer resistance protein
- SCRH
- sandwich-cultured rat hepatocytes
- HBSS
- Hanks' balanced salt solution
- LC-MS/MS
- liquid chromatography tandem mass spectrometry
- CDF
- 5 (and 6)-carboxy-2′,7′-dichlorofluorescein
- BEI
- biliary excretion index
- IVIVC
- in vitro-in vivo correlation.
- Received August 1, 2011.
- Accepted December 21, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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