Effect of omeprazole on diazepam disposition in the rat: in vitro and in vivo studies

Pharm Res. 1995 Nov;12(11):1642-6. doi: 10.1023/a:1016241000480.


Purpose: The inhibitory effects of omeprazole on diazepam metabolism in vitro and in vivo are compared in the rat.

Methods: 3-hydroxylation and N-demethylation of diazepam was investigated in the presence of a range of omeprazole concentrations (2-500 microM) in hepatic microsomes and hepatocytes. Zero order infusions together with matched bolus doses of omeprazole were used to achieve a range of steady state plasma concentrations (10-50mg/L) and to study the diazepam-omeprazole interaction in vivo.

Results: The 3-hydroxlation pathway was more prone to inhibition (KIs 108 +/- 30 and 28 +/- 11 microM in microsomes and hepatocytes, respectively) than the demethylation pathway (KIs of 226 +/- 76 and 59 +/- 27 microM in microsomes and hepatocytes, respectively). In both in vitro systems, the mechanism of inhibition was competitive with Km/KI ratios larger than 1 for the 3HDZ pathway and smaller than 1 for the NDZ pathway. There was an omeprazole concentration dependent decrease in diazepam clearance in vivo which could be modelled using a simple inhibition equation with a KI of 57 microM (19.8mg/L). In contrast there was no statistically significant change in the steady state volume of distribution for diazepam in the presence of omeprazole.

Conclusions: The in vivo KI for the omeprazole: diazepam inhibition interaction shows closer agreement with the KI values obtained in hepatocytes than with those observed in microsomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Anxiety Agents / metabolism*
  • Anti-Anxiety Agents / pharmacokinetics
  • Anti-Ulcer Agents / pharmacology*
  • Biotransformation
  • Chromatography, High Pressure Liquid
  • Diazepam / metabolism*
  • Diazepam / pharmacokinetics
  • Drug Interactions
  • In Vitro Techniques
  • Liver / cytology
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Microsomes, Liver / metabolism
  • Omeprazole / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Distribution


  • Anti-Anxiety Agents
  • Anti-Ulcer Agents
  • Omeprazole
  • Diazepam