Effect of Cimetidine and Phenobarbital on metabolite kinetics of Omeprazole in rats

Arch Pharm Res. 2005 Oct;28(10):1196-202. doi: 10.1007/BF02972986.


Omeprazole (OMP) is a proton pump inhibitor used as an oral treatment for acid-related gastrointestinal disorders. In the liver, it is primarily metabolized by cytochrome P-450 (CYP450) isoenzymes such as CYP2C19 and CYP3A4. 5-Hyroxyomeprazole (5-OHOMP) and omeprazole sulfone (OMP-SFN) are the two major metabolites of OMP in human. Cimetidine (CMT) inhibits the breakdown of drugs metabolized by CYP450 and reduces the clearance of coadministered drug resulted from both the CMT binding to CYP450 and the decreased hepatic blood flow due to CMT. Phenobarbital (PB) induces drug metabolism in laboratory animals and human. PB induction mainly involves mammalian CYP forms in gene families 2B and 3A. PB has been widely used as a prototype inducer for biochemical investigations of drug metabolism and the enzymes catalyzing this metabolism, as well as for genetic, pharmacological, and toxicological investigations. In order to investigate the influence of CMT and PB on the metabolite kinetics of OMP, we intravenously administered OMP (30 mg/kg) to rats intraperitoneally pretreated with normal saline (5 mL/kg), CMT (100 mg/kg) or PB (75 mg/kg) once a day for four days, and compared the pharmacokinetic parameters of OMP. The systemic clearance (CLt) of OMP was significantly (p<0.05) decreased in CMT-pretreated rats and significantly (p<0.05) increased in PB-pretreated rats. These results indicate that CMT inhibits the OMP metabolism due to both decreased hepatic blood flow and inhibited enzyme activity of CYP2C19 and 3A4 and that PB increases the OMP metabolism due to stimulation of the liver blood flow and/or bile flow, due not to induction of the enzyme activity of CYP3A4.

Publication types

  • Comparative Study

MeSH terms

  • Algorithms
  • Animals
  • Area Under Curve
  • Chromatography, High Pressure Liquid
  • Cimetidine / administration & dosage
  • Cimetidine / pharmacology*
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology
  • Injections, Intraperitoneal
  • Injections, Intravenous
  • Male
  • Models, Biological
  • Omeprazole / blood
  • Omeprazole / metabolism
  • Omeprazole / pharmacokinetics*
  • Phenobarbital / administration & dosage
  • Phenobarbital / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors


  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Cimetidine
  • Cytochrome P-450 Enzyme System
  • Omeprazole
  • Phenobarbital