✍ Scribed by Stefan Oswald; Christiane Koll; Werner Siegmund
No coin nor oath required. For personal study only.
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 (À/À) 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 AE 2.07 versus 2.09 AE 0.83 ng/ml, p < 0.001) but not of EZ (0.92 AE 0.73 versus 0.55 AE 0.40 ng/ml, n.s.). Consequently, urinary excretion of GLUC was about three-fold increased (9.96 AE 0.27 versus 3.10 AE 1.37 mg/day, p ¼ 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.
📜 SIMILAR VOLUMES
The absorption and disposition of fluvastatin have been studied in the female rabbit. In naive rabbits receiving a single oral dose (1 mg kg-I) of [3H]fluvastatin, absorption was rapid and amounted to c. 90 per cent compared with an intravenous reference dose. The drug was subject to considerable fi
## Abstract A subpopulation of the CF‐1 mouse strain is sensitive to neurotoxicity following exposure to avermectins, a family of structurally related antiparasitic agents. This unusual sensitivity is the result of a deficiency in the mdr1a P‐glycoprotein that normally contributes to a functional b
In the mouse, both the mdr1a and the mdr1b gene encode drug-transporting P-glycoproteins. The mdr1a P-glycoprotein is expressed in epithelial cells of, among others, the liver and the intestine. Furthermore, the mdr1b gene product is found in the liver but is not detectable in the intestine. To esta