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

J Pharm Sci. 2007 Dec;96(12):3478-84. doi: 10.1002/jps.20996.

Abstract

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 microg/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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / deficiency
  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism*
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Administration, Oral
  • Animals
  • Anticholesteremic Agents / administration & dosage
  • Anticholesteremic Agents / blood
  • Anticholesteremic Agents / pharmacokinetics*
  • Anticholesteremic Agents / urine
  • Azetidines / administration & dosage
  • Azetidines / blood
  • Azetidines / metabolism
  • Azetidines / pharmacokinetics*
  • Azetidines / urine
  • Biological Availability
  • Biotransformation
  • Cholesterol / metabolism*
  • Ezetimibe
  • Feces / chemistry
  • Glucuronides / metabolism
  • Intestinal Absorption / drug effects*
  • Kidney / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Tissue Distribution

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP-Binding Cassette Transporters
  • Anticholesteremic Agents
  • Azetidines
  • Glucuronides
  • P-glycoprotein 2
  • ezetimibe glucuronide
  • Cholesterol
  • multidrug resistance protein 3
  • Ezetimibe