Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 106, Issue 9, Pages 2815-2825Publisher
WILEY
DOI: 10.1016/j.xphs.2017.04.056
Keywords
hepatic clearance; hepatic transport; hepatobiliary disposition; hepatocytes; transporters
Funding
- GlaxoSmithKline within Centre for Applied Pharmacokinetic Research at the University of Manchester [R030001]
- Janssen within Centre for Applied Pharmacokinetic Research at the University of Manchester [R030001]
- Lilly within Centre for Applied Pharmacokinetic Research at the University of Manchester [R030001]
- Pfizer within Centre for Applied Pharmacokinetic Research at the University of Manchester [R030001]
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One of the most holistic in vitro systems for prediction of intracellular drug concentrations is sandwich-cultured hepatocytes (SCH); however, a comprehensive evaluation of the utility of SCH to estimate uptake and biliary clearances and the need for additional kinetic parameters has yet to be carried out. Toward this end, we have selected 9 compounds (rosuvastatin, valsartan, fexofenadine, pravastatin, repaglinide, telmisartan, atorvastatin, saquinavir, and quinidine) to provide a range of physicochemical and hepatic disposition properties. Uptake clearances were determined in SCH and compared with conventional monolayer and suspension hepatocyte systems, previously reported by our laboratory. CLuptake ranged from 1 to 41 mu L/min/10(6) cells in SCH which were significantly lower (1%-10%) compared with the other hepatocyte models. The hepatocyte-to-media unbound concentration ratio (Kp(u)) has been assessed and ranged 0.7-59, lower compared with other hepatocyte systems (8-280). Estimates of in vitro biliary clearance (CLbile) for 4 drugs were determined and were scaled to predict in vivo values using both intracellular concentration and media drug concentrations. These studies demonstrate that reduced uptake in rat SCH may limit drug access to canalicular efflux transport proteins and highlight the importance of elucidating the interplay between these proteins for accurate prediction of hepatic clearance. Crown Copyright (C) 2017 Published by Elsevier Inc. on behalf of the American Pharmacists Association. All rights reserved.
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