Effect of omeprazole on diazepam disposition in the rat: in vitro and in vivo studies.
OBJECTIVE
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.
Zomorodi
K
K
Department of Pharmacy, University of Manchester, UK.
Houston
J B
JB
D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003975:Diazepam / Q000378:metabolism* / Q000493:pharmacokinetics; D004347:Drug Interactions; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009853:Omeprazole / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D014151:Anti-Anxiety Agents; D000897:Anti-Ulcer Agents; D009853:Omeprazole; D003975:Diazepam