Omeprazole: effects on oxidative drug metabolism.

Abstract

Omeprazole, a substituted benzimidazole, and a potent inhibitor of gastric parietal cell H+/K+ ATPase, was tested for drug interactions at two dose levels (30 mg and 60 mg/day) in man using the model drugs [14C]‐aminopyrine and antipyrine. Elimination of both models was assessed before and after 15 days treatment with omeprazole. In addition [14C]‐aminopyrine metabolism was assessed on day 2 of treatment to investigate the rapidity of onset of any effect. In 10 healthy male volunteers omeprazole 60 mg/day for 14 days prolonged aminopyrine 14CO2 half life (t1/2), measured on the 15th day, by 21% (P less than 0.05), and reduced percent dose demethylated in 2 h (ABT2) by 19% (P less than 0.005). No effect was seen on day 2 of therapy. After 14 days treatment antipyrine half‐life was prolonged by 10% (P less than 0.025) and clearance was reduced by 14% (P = 0.063). In nine healthy male volunteers omeprazole 30 mg/day for 14 days prolonged aminopyrine 14CO2 by 13% and reduced ABT2 by 11%. Both changes just failed to reach statistical significance. At this dose antipyrine metabolism was unaltered. As the dose of omeprazole used in clinical practice may be less than 30 mg/day it is unlikely that metabolic inhibition will occur during routine use, although it will be necessary to test for interactions with therapeutically more important compounds. Interactions should be looked for when large doses of omeprazole are being used to treat hypersecretory states.

Oral phenytoin pharmacokinetics during omeprazole therapy.

“…Previous work, however, suggests that omeprazole could significantly interfere with the hepatic elimination of phenytoin: omeprazole 60 mg day-' impairs antipyrine clearance by 14%, although no significant change occurs with a lower dose (30 mg day-1) (Henry et al, 1984); and omeprazole (40 mg day-1) decreases the clearance of intravenous phenytoin by 15% and increases the apparent elimination half-life by 27% (Gugler & Jensen, 1985). In our study, although the mean apparent elimination half-life of phenytoin was increased in 8 of the 10 subjects whilst on omeprazole the change was not sufficient to reach significance.…”

“…It is effective in healing peptic ulcers at doses ranging from 10 mg to 60 mg per day (Prichard et al, 1985). A recent study has shown that omeprazole impairs the plasma clearance of both diazepam and phenytoin when given intravenously (Gugler & Jensen, 1985), possibly through inhibition of hepatic cytochrome P-450 mono-oxygenases, there being evidence that the benzimidazole moiety binds to microsomal cytochrome P-450 (Dickens & Bridges, 1982), and that omeprazole impairs antipyrine clearance in a dose-related manner (Henry et al, 1984).…”

Omeprazole and Cytochrome P450-Dependent Hepatic Metabolism: A Comparison of Endogenous and Exogenous Substrates in Male Rats

“…The resulting pro longed reduction in gastric acidity has been useful in the therapy of gastroesophageal re flux disease and in hypersecretory condi tions such as the Zollinger-Ellison syndrome. Early studies in humans showed that the administration of omeprazole was associ ated with prolongation of the half-lives of aminopyrine [1], diazepam and phenytoin [2,3], Omeprazole has also been shown to significantly depress the peak cortisol re sponse 1 h after treatment with ACTH in male volunteers [4], Additionally, it has been reported that omeprazole inhibits 7-ethoxycoumarin de-ethylation in vitro in both hu man [5] and rat [6] liver microsomes.…”

Lansoprazole does not affect the bioavailability of oral contraceptives.

“…Omeprazole, for instance, dose-dependently inhibits the hepatic elimination of diazepam [3,4], carbamazepine [5], possibly of phenytoin [3, [6][7][8], and to a small extent that of aminopyrine [9] and (R)-warfarin [10]. It also induces the expression and activity of cytochromes P450 lAl/2 [11][12][13][14], inhibits adrenocortical steroidogenesis [15] but fails to alter 2-hydroxylation of oestradiol in males [16].…”

“…While antipyrine clearance is slightly reduced with omeprazole [9] and slightly increased with lansoprazole [19], theophylline clearance is marginally increased with both drugs [20,21].…”