RT Journal Article
SR Electronic
T1 In Vivo Biliary Clearance Should Be Predicted by Intrinsic Biliary Clearance in Sandwich-Cultured Hepatocytes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 602
OP 609
DO 10.1124/dmd.111.042101
VO 40
IS 3
A1 Masanori Nakakariya
A1 Midori Ono
A1 Nobuyuki Amano
A1 Toshiya Moriwaki
A1 Kazuya Maeda
A1 Yuichi Sugiyama
YR 2012
UL http://dmd.aspetjournals.org/content/40/3/602.abstract
AB 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.