RT Journal Article
SR Electronic
T1 Hepatic Basolateral Efflux Contributes Significantly to Rosuvastatin Disposition II: Characterization of Hepatic Elimination by Basolateral, Biliary, and Metabolic Clearance Pathways in Rat Isolated Perfused Liver
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 737
OP 745
DO 10.1124/jpet.113.208314
VO 347
IS 3
A1 Nathan D. Pfeifer
A1 Arlene S. Bridges
A1 Brian C. Ferslew
A1 Rhiannon N. Hardwick
A1 Kim L. R. Brouwer
YR 2013
UL http://jpet.aspetjournals.org/content/347/3/737.abstract
AB Basolateral efflux clearance (CLBL) contributes significantly to rosuvastatin (RSV) elimination in sandwich-cultured hepatocytes (SCH). The contribution of CLBL 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 (CLBile) was ablated almost completely by GF120918 in TR− IPLs, confirming that Mrp2 and Bcrp primarily are responsible for RSV CLBile. RSV appearance in outflow perfusate was attributed primarily to CLBL, which was impaired in TR− IPLs. CLBL was ∼6-fold greater than CLBile 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 CLBL and CLBile. 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 CLBL were 4.2- and 6.4-fold lower, respectively, in rat SCH compared with IPLs; CLBile translated almost directly (1.1-fold). The present IPL data confirmed the significant role of CLBL in RSV hepatic elimination, and demonstrated that both CLBL and CLBile influence RSV hepatic and systemic exposure.