Inhibition of human liver cytochrome P‐450 by omeprazole.

Jensen, J.Chris; Gugler, R

doi:10.1111/j.1365-2125.1986.tb05199.x

Cited by 41 publications

(15 citation statements)

References 14 publications

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“…It is however unlikely that the omeprazole inhibitable parts of these reactions are carried out by the same P450 since the Ki values of omeprazole are 13-35 times higher and sulphaphenazole has no effect on these reactions. The fact that omeprazole inhibits more than one single human cytochrome P450 has been described before by Jensen & Gugler (1986).…”

Section: Discussionmentioning

confidence: 99%

Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics

Hermans

Thijssen

1993

British J Pharmacology

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1 To explain the large differences in (the stereoselectivity of) the clearances of the enantiomers of warfarin and acenocoumarol (4'-nitrowarfarin) their human liver microsomal metabolism has been studied and enzyme kinetic parameters determined. The effects of cimetidine, propafenone, sulphaphenazole, and omeprazole on their metabolism has been investigated. 2 The 4-hydroxycoumarins follow similar metabolic routes and are mainly hydroxylated at the 6-and 7-position (accounting for 63 to 99% of the metabolic clearances).3 Due to the lower Km values of R-and S-acenocoumarol and higher Vma. values of S-acenocoumarol, the overall metabolic clearances of R/S acenocoumarol exceed those of R/S warfarin 6 and 66 times respectively. 4 The metabolism of both compounds is stereoselective for the S-enantiomers, which is 10 times more pronounced in the case of acenocoumarol.5 Except for the 7-hydroxylation of the R-enantiomers (r = 0.90; P <0.025), the 6-and 7-hydroxylation rates of R/S warfarin do not correlate with those of R/S acenocoumarol. 6 Sulphaphenazole competitively inhibits the 7-and in some samples partly (up to 50%) the 6-hydroxylation of S-warfarin as well as the 7-hydroxylation of R-and S-acenocoumarol and the 6-hydroxylation of S-acenocoumarol (Kis ranging from 0.5-1.3 JAM).7 Omeprazole partly (40-80%) inhibits the 6-and 7-hydroxylation of R-warfarin (Ki = 99 and 117 pM) and of R-(Ki = 219 and 7.2 jAM) and S-acenocoumarol (Ki = 6.1 and 7.7 JiM) but not S-warfarin in a competitive manner. 8 Differences in the partial (up to 40%) inhibition of the metabolism of the enantiomers of the 4-hydroxycoumarins were also observed for the relatively weak inhibitors, propafenone and cimetidine. 9 The results suggest that the coumarin ring hydroxylations of both compounds are catalysed by different combinations of P450 isozymes. The 7-hydroxylation of R/S acenocoumarol and the 6-hydroxylation of S-acenocoumarol are at least partly conducted by (a) P450 isozyme(s) of the 2C subfamily different from P450 2C9 (the main S-warfarin 7-and 6-hydroxylase).

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Section: Discussionmentioning

confidence: 99%

Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics

Hermans

Thijssen

1993

British J Pharmacology

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“…First, the decreased intragastric acidity resulting from inhibition of the hydrogen/potassium ATPase in the stomach may alter the absorption of other drugs. Second, as omeprazole is metabolized almost entirely by the hepatic cytochrome P450 system, it may change the clearance of other drugs by inhibition or induction of other P450-linked enzymes [20]. Finally, about 80% of a given dose of omeprazole is excreted in the urine [18], and this may decrease the renal elimination of other substances.…”

Section: Introductionmentioning

confidence: 99%

Effect of Omeprazole on the Pharmacokinetics of Oral Gemifloxacin in Healthy Volunteers

Allen

Vousden²,

Lewis

1999

Chemotherapy

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This randomized, double-blind, 2-way crossover study investigated the effect of omeprazole on the pharmacokinetics of gemifloxacin, a novel fluoroquinolone. Thirteen healthy male volunteers received a 320 mg oral dose of gemifloxacin after 4 days of dosing with either omeprazole (40 mg once daily) or matching placebo. Blood was sampled for 48 h after dosing for determination of pharmacokinetic parameters. The mean area under the plasma concentration-time curve extrapolated to infinity (AUC_0–∞) and maximum plasma concentration (C_max) for gemifloxacin were increased by, on average, 10% (90% confidence interval [CI], 0.89, 1.36) and 11% (90% CI, 0.87, 1.43), respectively, when gemifloxacin was given after omeprazole compared with after placebo. Neither the time to C_max (T_max) nor the half-life of gemifloxacin appeared to be affected by administration of omeprazole. There were no clinically relevant changes in adverse events, vital signs or the results of laboratory investigations after co-administration of omeprazole compared with placebo. In view of the modest increase in systemic exposure and the likely maximal increases indicated by the CIs, the effect of omeprazole on gemifloxacin pharmacokinetics is not considered to be clinically significant. Gemifloxacin and omeprazole can therefore be co-administered with no requirement for a dose adjustment.

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“…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: 99%

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

Galbraith

Michnovicz²

1993

Pharmacology

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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.

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Inhibition of human liver cytochrome P‐450 by omeprazole.

Cited by 41 publications

References 14 publications

Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics

Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics

Effect of Omeprazole on the Pharmacokinetics of Oral Gemifloxacin in Healthy Volunteers

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

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