K. Zomorodi et Jb. Houston, EFFECT OF OMEPRAZOLE ON DIAZEPAM DISPOSITION IN THE RAT - IN-VITRO AND IN-VIVO STUDIES, Pharmaceutical research, 12(11), 1995, pp. 1642-1646
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.