Disposition of the cholesterol absorption inhibitor ezetimibe in mdr1a/b (−/−) mice

The lipid lowering agent ezetimibe (EZ) and its intestinally formed glucuronide (GLUC) were shown to be substrates of the efflux transporters P‐glycoprotein (P‐gp) and the multidrug resistance associated protein 2 (MRP2) which markedly influences the disposition and efficacy of EZ in man. This study aims to elucidate the unique meaning of P‐gp in the pharmacokinetics of EZ in mice. In brief, serum concentrations, organ distribution and elimination of EZ were determined in 10 male wild‐type and mdr1a/b (−/−) mice after oral treatment with EZ (10 mg/kg, 10 days). EZ and GLUC were quantified in serum, urine, feces and various tissues using a validated LC‐MS/MS method. Compared to wild‐type mice, mdr1a/b knockout was associated with significantly increased serum concentrations of GLUC (5.58 ± 2.07 versus 2.09 ± 0.83 ng/ml, p < 0.001) but not of EZ (0.92 ± 0.73 versus 0.55 ± 0.40 ng/ml, n.s.). Consequently, urinary excretion of GLUC was about three‐fold increased (9.96 ± 0.27 versus 3.10 ± 1.37 µg/day, p = 0.049) whereas renal clearance and the amount excreted via feces remained unchanged. Both EZ and GLUC were not over‐proportionally distributed into investigated organs. P‐glycoprotein primary influences the oral absorption of ezetimibe in mice. Distribution, renal and fecal excretion of the drug seems not to be markedly affected by P‐glycoprotein. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 3478-3484, 2007