In Vivo Biliary Clearance Should Be Predicted by Intrinsic Biliary Clearance in Sandwich-Cultured Hepatocytes

Abstract

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 (CL bile, app ) from sandwichcultured rat hepatocytes (SCRH) based on medium concentrations correlates to in vivo CL bile, app based on plasma concentrations of angiotensin II receptor blockers (ARBs), HMG-CoA reductase inhibitors (statins), ␤-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 sandwichcultured hepatocytes. To evaluate this issue, intrinsic biliary clearance (CL bile, int ) based on intracellular compound concentrations was evaluated to investigate the in vitro-in vivo correlation of this process among ARBs, statins, ␤-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 CL bile, int (0.7-6-fold) were much smaller than those of CL bile, app (7-300-fold). Therefore, in vivo CL bile, int is more accurately reflected using SCRH than CL bile, app . In conclusion, to predict in vivo biliary clearance more accurately, CL bile, int should be evaluated instead of CL bile, app between SCRH and in vivo.

Species Differences in Biliary Clearance and Possible Relevance of Hepatic Uptake and Efflux Transporters Involvement

“…Advancements have been made in using this in vitro technique for predicting biliary clearance (Abe et al, 2009), but the robustness of the method is still to be extensively tested with a wide range of drugs. However, appreciation of the intracellular drug concentrations and calculation of an in vitro biliary intrinsic clearance may see the method emerge as a truly predictive tool (Nakakariya et al, 2012). Nonetheless, preclinical in vivo data retain an extremely important role in facilitating the understanding and contextualization of the risks associated with human pharmacokinetic predictions.…”

Prediction of In Vivo Rat Biliary Drug Clearance from an In Vitro Hepatocyte Efflux Model

“…Earlier attempts to scale rat in vivo CL bile from rat SCH efflux, incorporating fu blood , for the biliary cleared compound set resulted in 1.6-fold (digoxin), 3.5-fold (fexofenadine), and 15-to 17-fold (rosuvastatin) underpredictions (Annaert et al, 2001;Turncliff et al, 2006;Fukuda et al, 2008;Nakakariya et al, 2012). Nakakariya et al (2012) have recently shown that biliary clearance predictions from rat SCH can be considerably improved by predicting biliary intrinsic clearance using liver tissue drug concentrations and free intracellular concentrations in rat SCH. Predicting rat CL bile using rat SCH efflux in the traditional manner yielded underpredictions ranging from 7-fold to 300-fold.…”

“…Predicting rat CL bile using rat SCH efflux in the traditional manner yielded underpredictions ranging from 7-fold to 300-fold. Predicting intrinsic biliary efflux using intracellular SCH and liver concentrations improved the results, giving underpredictions with an average fold error of 4.5, representing the most successful in vitro method to date for the prediction of biliary clearance (Nakakariya et al, 2012).…”

“…The excretion of compounds into the canalicular compartment is used to calculate the biliary excretion (Liu et al, 1999;De Bruyn et al, 2013). This strategy has been successful in predicting the bile efflux of several drugs, but as noted by Li et al (2010) and others, it often underpredicts biliary clearance by 10-fold to 100-fold (Nakakariya et al, 2012;De Bruyn et al, 2013). Partly this may be due to the down-regulation of both dx.doi.org/10.1124/dmd.113.054155. drug uptake and efflux transporters that has been demonstrated to take place within the first days after the plating of hepatocytes from both rats and humans (Liu et al, 1998;Li et al, 2009a;Kotani et al, 2011;Tchaparian et al, 2011;Kimoto et al, 2012;De Bruyn et al, 2013).…”

Hepatobiliary Secretion Kinetics of Conjugated Bile Acids Measured in Pigs by 11C-Cholylsarcosine PET

“…However, studying hepatobiliary uptake and secretion of bile acids in vivo is difficult. Isotopically labeled bile acids have been used to study bile acid uptake and secretion in the isolated perfused rat liver (7,8) and conscious dogs (9), and sandwich cultures have been used in attempts to predict the in vivo kinetics of bile acid turnover (10)(11)(12). Clinical methods, such as 99m Tc-mebrofenin SPECT (13) and novel PET tracers for hepatic drug transporters (14), have been used to assess different aspects of hepatic excretory function but not specific bile acid transporters.…”