title: In vivo biliary clearance should be predicted by intrinsic biliary clearance in sandwich-cultured hepatocytes.
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 sandwich- cultured 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), 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 (CL(bile, 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 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.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan. nakakariya_masanori@takeda.co.jp
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakakariya
authors.forename: Midori
authors.initials: M
authors.lastname: Ono
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Amano
authors.forename: Toshiya
authors.initials: T
authors.lastname: Moriwaki
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001659:Biliary Tract / Q000378:metabolism*; D001692:Biological Transport; D002478:Cells, Cultured; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019772:Topotecan / Q000378:metabolism; D047090:beta-Lactams / Q000378:metabolism
chemical_list: D057911:Angiotensin Receptor Antagonists; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D004364:Pharmaceutical Preparations; D047090:beta-Lactams; D019772:Topotecan