The interaction of omeprazole with rat liver cytochrome P450-mediated monooxygenase reactions in vitro and in vivo

Chenery, Richard J.; Ayrton, Andrew D.; Oldham, Harriet G.; Norman, S.J.; Standring, P.

doi:10.1016/0006-2952(88)90801-5

Cited by 25 publications

(12 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, if only the 4Ј-HDZ pathway had been considered, the interaction would have been overpredicted, whereas consideration of all three pathways gave the best prediction. In addition, the depletion results (Table 2) were consistent with those from Chenery et al (1988), who demonstrated that the addition of 50 M OMP to DZ rat hepatocyte incubations results in a 67 to 79% reduction of DZ clearance. However, one complication associated with the prediction of inhibition using this method is the inability to distinguish between inhibition caused by the inhibitor and associated inhibitory effects from substrate/inhibitor metabolites.…”

Section: Discussionsupporting

confidence: 86%

Quantitative Prediction of the in Vivo Inhibition of Diazepam Metabolism by Omeprazole Using Rat Liver Microsomes and Hepatocytes

Jones

Hallifax²,

Houston³

2004

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:The diazepam (DZ)-omeprazole (OMP) interaction has been selected as a prototype for an important drug-drug interaction involving cytochrome P450 inhibition. The availability of an in vivo K i value (unbound K i , 21 M) obtained from a series of steady-state inhibitor infusion studies allowed assessment of several in vitroderived predictions of this inhibition interaction. Studies monitoring substrate depletion with time were used to obtain in vitro K i values that were evaluated against the more traditional metabolite formation approach using microsomes and hepatocytes. OMP in- The inhibition of diazepam (DZ 1 ) metabolism by omeprazole (OMP) has been well documented in vivo; therapeutic concentrations of OMP have been reported to decrease the plasma clearance of DZ both in humans (Gugler and Jensen, 1985; Andersson et al., 1990a,b) and in rats . measured the in vivo clearance of DZ (administered by the hepatic portal vein) in rats receiving intravenous infusions together with matching bolus doses of OMP to achieve a wide range of steady-state plasma concentrations (10 -50 g/ml). The inhibition was modeled using a simple inhibition model (eq. 1) and the in vivo K i was calculated to be 57 M.where CL and CL 0 represent DZ clearance in the presence and absence of OMP, respectively, I ss represents the steady-state total plasma concentration of OMP, and K i represents the inhibition constant. Figure 1 shows the relationship between DZ clearance and steady-state unbound concentration of OMP achieved in this study. Such a detailed in vivo inhibition study is only possible in animals. In humans, inhibition studies are normally performed using one inhibitor oral dosing regimen, and the ratio of the AUC in the presence and absence of the inhibitor is used to assess the degree of interaction (Gugler and Jensen, 1985;

show abstract

Section: Discussionsupporting

confidence: 86%

Quantitative Prediction of the in Vivo Inhibition of Diazepam Metabolism by Omeprazole Using Rat Liver Microsomes and Hepatocytes

Jones

Hallifax²,

Houston³

2004

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…Similar results were seen following oral treatment of rats with ome prazole (500 mg/ kg b.w. for 14 days) in which ethoxycoumarin-O-deethylase activity was increased [6],…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

Galbraith

Jellinck²

1991

Pharmacology

View full text Add to dashboard Cite

Omeprazole, a benzimidazole compound which inhibits H⁺/K⁺ ATPase in the gut, is used in the treatment of gastroesophageal reflux disease. Clinical and experimental use of omeprazole has been associated with inhibition of the cytochrome P450-dependent metabolism of a few drugs both in vivo in man and in vitro in animals. In these experiments, in vivo administration of omeprazole to rats failed to inhibit the cytochrome P450-dependent metabolism of four prototypic drugs, testosterone or estradiol.

show abstract

“…Omeprazole has been useful in the therapy of gastroesophageal reflux and the Zollinger-Ellison syndrome, and may prove beneficial in the treatment of [2] and phcnytoin [3] in vivo in humans. Ome prazole also inhibits the in vitro deethylation of 7-ethoxycoumarin in both human [4] and rat [5] liver microsomes. Additionally, ome prazole administration is associated with a depressed peak cortisol response after treat ment of normal male volunteers with ACTH [6],…”

Section: Introductionmentioning

confidence: 95%

Omeprazole Fails to Alter the Cytochrome P450-Dependent 2-Hydroxylation of Estradiol in Male Volunteers

Galbraith

Michnovicz²

1993

Pharmacology

View full text Add to dashboard Cite

Omeprazole, a proton pump inhibitor, is used in the treatment of gastrointestinal diseases associated with hyperacidity. It binds to, and inhibits, some of the activities of hepatic cytochrome P450 resulting in increased half-lives of certain pharmacologic and endogenous compounds. It may also increase the activity of cytochrome P450 under certain conditions. Oxidative metabolism of endogenous estrogens, particularly the 2-hydroxylation pathway, is P450-dependent, and is highly sensitive to a variety of dietary and pharmacologic agents. We therefore studied the extent of estradiol 2-hydroxylation in 7 normal male volunteers before and during oral treatment with omeprazole 20 mg twice daily. Using a specific in vivo radiometric assay, the mean extent (±SEM) of estradiol 2-hydroxylation was found to be unchanged before and after omeprazole treatment (27.3 ± 3.0 vs. 27.5 ± 3.4%, respectively). The excretion of the endogenous urinary estrogen metabolites, 2-hydroxyestrone, estriol, and estrone was also unaltered by omeprazole. These results show that omeprazole, in contradistinction to other medications used in the treatment of peptic ulcer disease, is without effect on estradiol metabolism in men.

show abstract

The interaction of omeprazole with rat liver cytochrome P450-mediated monooxygenase reactions in vitro and in vivo

Cited by 25 publications

References 18 publications

Quantitative Prediction of the in Vivo Inhibition of Diazepam Metabolism by Omeprazole Using Rat Liver Microsomes and Hepatocytes

Quantitative Prediction of the in Vivo Inhibition of Diazepam Metabolism by Omeprazole Using Rat Liver Microsomes and Hepatocytes

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

Omeprazole Fails to Alter the Cytochrome P450-Dependent 2-Hydroxylation of Estradiol in Male Volunteers

Contact Info

Product

Resources

About