Abstract

Basolateral efflux clearance (CL_BL) contributes significantly to rosuvastatin (RSV) elimination in sandwich-cultured hepatocytes (SCH). The contribution of CL_BL to RSV hepatic elimination was determined in single-pass isolated perfused livers (IPLs) from wild-type (WT) and multidrug resistance–associated protein 2 (Mrp2)-deficient (TR⁻) rats in the absence and presence of the P-glycoprotein and breast cancer resistance protein (Bcrp) inhibitor, elacridar (GF120918); clearance values were compared with SCH. RSV biliary clearance (CL_Bile) was ablated almost completely by GF120918 in TR⁻ IPLs, confirming that Mrp2 and Bcrp primarily are responsible for RSV CL_Bile. RSV appearance in outflow perfusate was attributed primarily to CL_BL, which was impaired in TR⁻ IPLs. CL_BL was ∼6-fold greater than CL_Bile in the linear range in WT IPLs in the absence of GF120918. Recovery of unchanged RSV in liver tissue increased in TR⁻ compared with WT (∼25 versus 6% of the administered dose) due to impaired CL_BL and CL_Bile. RSV pentanoic acid, identified by high-resolution liquid chromatography–tandem mass spectroscopy, comprised ∼40% of total liver content and ∼16% of the administered dose in TR⁻ livers at the end of perfusion, compared with ∼30 and 3% in WT livers, consistent with impaired RSV excretion and “shunting” to the metabolic pathway. In vitro–ex vivo extrapolation between WT SCH and IPLs (without GF120918) revealed that uptake clearance and CL_BL were 4.2- and 6.4-fold lower, respectively, in rat SCH compared with IPLs; CL_Bile translated almost directly (1.1-fold). The present IPL data confirmed the significant role of CL_BL in RSV hepatic elimination, and demonstrated that both CL_BL and CL_Bile influence RSV hepatic and systemic exposure.