PMID: 8592663Nov 1, 1995Paper

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

Pharmaceutical Research
K Zomorodi, J B Houston

Abstract

The inhibitory effects of omeprazole on diazepam metabolism in vitro and in vivo are compared in the rat. 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. 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. The in vivo KI f...Continue Reading

Citations

Feb 27, 1999·Journal of Clinical Pharmacy and Therapeutics·E Tanaka
Apr 22, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hannah M JonesJ Brian Houston
Sep 3, 2003·European Journal of Biochemistry·Annalise Di MarcoRalph Laufer
Jan 7, 2004·Drug Metabolism Reviews·J Brian Houston, Aleksandra Galetin
Mar 18, 2004·British Journal of Clinical Pharmacology·Kiyomi ItoJ Brian Houston
Mar 13, 2016·Journal of Veterinary Pharmacology and Therapeutics·S M M NakayamaM Ishizuka
Jan 1, 1997·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·K Zomorodi, J B Houston
Mar 25, 2004·Clinical Therapeutics·Mitchell J Spirt
Oct 22, 2008·Nutrition & Metabolism·Zakia Bibi

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