EFFECT OF OMEPRAZOLE ON DIAZEPAM DISPOSITION IN THE RAT - IN-VITRO AND IN-VIVO STUDIES

Purpose. The inhibitory effects of omeprazole on diazepam metabolism i n 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 mu M) in hepatic microsomes and hepatocytes. Zero order infusions together with matched bolus dose s of omeprazole were used to achieve a range of steady state plasma co ncentrations (10-50 mg/L) and to study the diazepam-omeprazole interac tion in vivo. Results. The 3-hydroxlation pathway was more prone to in hibition (K(I)s 108 +/- 30 and 28 +/- 11 mu M in microsomes and hepato cytes, respectively) than the demethylation pathway (K(I)s of 226 +/- 76 and 59 +/- 27 mu M in microsomes and hepatocytes, respectively). In both in vitro systems, the mechanism of inhibition was competitive wi th Km/K-I 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 K-I of 57 mu M (19.8mg/L). In contr ast there was no statistically significant change in the steady state volume of distribution for diazepam in the presence of omeprazole. Con clusions. The in vivo K-I for the omeprazole: diazepam inhibition inte raction shows closer agreement with the K-I values obtained in hepatoc ytes than with those observed in microsomes.