Effect of gemfibrozil on the metabolism of pitavastatin--determining the best animal model for human CYP and UGT activities

Drug Metabol Drug Interact. 2004;20(1-2):25-42. doi: 10.1515/dmdi.2004.20.1-2.25.

Abstract

A series of studies was conducted to determine the best animal model for human CYP and UGT activities. The investigation focused primarily on the interactions occurring in the CYP- or UGT-mediated metabolism of pitavastatin, and involved in vitro and in vivo experiments. We found that the best animal models for human CYP-mediated hydroxylation and UGT-mediated lactonization of pitavastatin were rats and dogs, respectively. In addition, a large difference in the metabolic properties of pitavastatin was found between monkeys and humans. In the presence of gemfibrozil, the CYP- or UGT-mediated metabolism of pitavastatin was inhibited in vitro. However, gemfibrozil treatment had no inhibitory effect on the AUC of pitavastatin and its lactone form in rats and dogs. We conclude that the plasma level of pitavastatin would not be increased by co-administration of gemfibrozil in humans.

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases / immunology
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Dogs
  • Enzyme Inhibitors / metabolism*
  • Gemfibrozil / pharmacology*
  • Glucuronosyltransferase / metabolism
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / metabolism
  • Hypolipidemic Agents / pharmacology*
  • Immune Sera / immunology
  • Lactones / metabolism
  • Macaca fascicularis
  • Male
  • Metabolic Clearance Rate
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Models, Animal
  • Quinolines / antagonists & inhibitors
  • Quinolines / metabolism*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Enzyme Inhibitors
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Hypolipidemic Agents
  • Immune Sera
  • Lactones
  • Quinolines
  • Aryl Hydrocarbon Hydroxylases
  • Glucuronosyltransferase
  • pitavastatin
  • Gemfibrozil