title: Comparison of in vitro-in vivo extrapolation of biliary clearance using an empirical scaling factor versus transport-based scaling factors in sandwich-cultured rat hepatocytes.
abstract: Biliary clearance (CLb ) is often underestimated by in vitro-in vivo extrapolation from sandwich-cultured hepatocytes (SCHs). The objective of this study was to compare the performance of a universal correction factor with transporter-based correction factors in correcting underestimation of CLb . The apparent in vitro CLb of a training set of 21 compounds was determined using the SCH model and extrapolated to apparent in vivo CLb (CLb, app ). A universal correction factor (10.2) was obtained by a linear regression of the predicted CLb, app and observed in vivo CLb of training set compounds and applied to an independent test set (n = 20); the corrected CLb predictions of 13 compounds were within twofold error of observed values. Furthermore, two transporter-based correction factors (Organic anion transporting polypeptides/multidrug-resistance-related protein 2 and diffusion/P-glycoprotein) were estimated by linear regression analysis of training set compounds. The applications of the two correction factors to the test set resulted in improved prediction precision. In conclusion, both the universal correction factor and transporter-based correction factors provided reasonable corrections of CLb values, which are often underestimated by the SCH model. The use of transporter-based correction factors resulted in an even greater improvement of predictions for compounds with intermediate-to-high CLb values.
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zou
authors.forename: Xingrong
authors.initials: X
authors.lastname: Liu
authors.forename: Susan
authors.initials: S
authors.lastname: Wong
authors.forename: Meihua Rose
authors.initials: MR
authors.lastname: Feng
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Liederer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D022781:Hepatocytes / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D026901:Membrane Transport Proteins; D004364:Pharmaceutical Preparations
keywords: P-glycoprotein; biliary excretion; clearance; drug transport; hepatobiliary disposition; hepatocytes; in vitro/in vivo correlations (IVIVC); organic aniontransporting polypeptide transporters