Interphenotype differences in disposition and effect on gastrin levels of omeprazole—suitability of omeprazole as a probe for CYP2C19.

Chang, Ming; Tybring, Gunnel; Ml, Dahl; Götharson, E.; Sagar, Mohamed; Seensalu, R; Bertilsson, Leif

doi:10.1111/j.1365-2125.1995.tb04488.x

Cited by 173 publications

(160 citation statements)

References 30 publications

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Section: Introductionmentioning

confidence: 99%

“…Omeprazole is primarily metabolized by cytochrome P450, family 2, subfamily C, and polypeptide 19 (CYP2C19) and partially metabolized by CYP3A4 [11][12][13]. Three CYP2C19 genotypes have been identified: homozygous extensive metabolizer (homo EM), heterozygous extensive metabolizer (hetero EM) and poor metabolizer (PM) [12,13]. Several studies have reported that the metabolism of omeprazole is influenced by the CYP2C19 genotype, resulting in interindividual variabilities in the pharmacokinetics and pharmacodynamics of omeprazole [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…Three CYP2C19 genotypes have been identified: homozygous extensive metabolizer (homo EM), heterozygous extensive metabolizer (hetero EM) and poor metabolizer (PM) [12,13]. Several studies have reported that the metabolism of omeprazole is influenced by the CYP2C19 genotype, resulting in interindividual variabilities in the pharmacokinetics and pharmacodynamics of omeprazole [11][12][13]. Accordingly, the genetic polymorphism of CYP2C19 should be of clinical concern in the treatment of acid-related diseases with proton pump inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Influence of the Meal and Genotype of CYP2C19 on the Pharmacokinetics of Proton Pump Inhibitors in Healthy Japanese Subjects

Shinkai¹,

Koike²,

Shimada³

et al. 2013

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Objectives: To evaluate the influence of meals on the pharmacokinetics of omeprazole and rabeprazole and to investigate these PPIs with reference to CYP2C19 genotypes in healthy Japanese men. Methods: This was a randomized, open label, four-way crossover study. Twelve healthy Japanese male volunteers received a single oral dose of either 20 mg omeprazole or 10 mg rabeprazole, in the fasted state and after a standardized breakfast. Results: Between the administration of omeprazole in the fasted state and after breakfast, there were no significant differences in Cmax, AUC, Tmax, and half-life. Between the administration of rabeprazole in the fasted state and after breakfast, there were no significant differences in Cmax, AUC and half-life, whereas the Tmax of rabeprazole after breakfast was significantly delayed (2.8 ± 1.0 vs 5.3 ± 1.8 h, respectively; p = 0.006). PMs demonstrated the highest Cmax and AUC after drug intake under the fasting state and after breakfast, and homo EMs showed a significantly delayed Tmax. Conclusion: When a single dose of either PPI was administered, the pharmacokinetics of omeprazole was not affected by the meal, whereas the Tmax of rabeprazole after the meal was significantly delayed.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Influence of the Meal and Genotype of CYP2C19 on the Pharmacokinetics of Proton Pump Inhibitors in Healthy Japanese Subjects

Shinkai¹,

Koike²,

Shimada³

et al. 2013

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“…Given the favourable safety profile of omeprazole 15, the observed increase in exposure is unlikely to increase adverse event risk. This increase is suggestive of weak in vivo CYP2C19 inhibition over the study period, which is unlikely to be related to belatacept administration, but rather to omeprazole‐mediated, time‐dependent inhibition of its own CYP‐mediated elimination 16, 17. In support of this, model simulations of omeprazole 40 mg administered orally on Days 1, 4, 7 and 11 and without belatacept predicted considerable accumulation of omeprazole.…”

Section: Discussionmentioning

confidence: 80%

Use of a cocktail probe to assess potential drug interactions with cytochrome P450 after administration of belatacept, a costimulatory immunomodulator

Williams

Tao

Zhu

et al. 2016

Brit J Clinical Pharma

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AimThis open‐label study investigated the effect of belatacept on cytokine levels and on the pharmacokinetics of caffeine, losartan, omeprazole, dextromethorphan and midazolam, as CYP probe substrates after oral administration of the Inje cocktail in healthy volunteers.MethodsTwenty‐two evaluable subjects received the Inje cocktail on Days 1, 4, 7 and 11 and belatacept infusion on Day 4.ResultsSince belatacept caused no major alterations to cytokine levels, there were no major effects on CYP‐substrate pharmacokinetics, except for a slight (16–30%) increase in omeprazole exposure, which was probably due to omeprazole‐mediated, time‐dependent CYP inhibition. Belatacept did not cause major alterations in the pharmacokinetics, as measured by the geometric mean ratios and associated 90% confidence interval for area under the plasma concentration ‐time curve from time zero to infinity on Day 7 comparing administration with and without belatacept for caffeine (1.002 [0.914, 1.098]), dextromethorphan (1.031 [0.885, 1.200]), losartan (1.016 [0.938, 1.101)], midazolam (0.968 [0.892, 1.049]) or their respective metabolites.ConclusionsTherefore, no dose adjustments of CYP substrates are indicated with belatacept coadministration.

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“…19) Although there were no serious adverse events after single dose of omeprazole 80 mg in extensive metabolizers, multiple doses of 80 mgϫ 2/d for 1 week might be much enough in anti-H. pylori therapy. 20) Further studies on efficacy and safety should be undertaken to estimate the optimal dose of omeprazole.…”

Section: Discussionmentioning

confidence: 99%

Optimal Dose of Omeprazole for CYP2C19 Extensive Metabolizers in Anti-Helicobacter pylori Therapy: Pharmacokinetic Considerations.

Kita

Sakaeda

Aoyama

et al. 2002

Biological & Pharmaceutical Bulletin

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Proton pump inhibitors are occasionally used in therapy for eradicating Helicobacter pylori in the combination with antimicrobials, [1][2][3][4][5] for the prevention of gastric and duodenal ulcer diseases.1,2) Triple therapy using omeprazole, amoxicillin, and clarithromycin is now recommended for anti-H. pylori therapy because of its high eradication rate (greater than 90%), [3][4][5] although problems with this therapy have arisen including the resistance of H. pylori to clarithromycin by failure. 2,3)Omeprazole is extensively metabolized into the primary metabolites of 5Ј-hydroxyomeprazole and omeprazole sulfone (Fig. 1). Formation of the 5Ј-hydroxyomeprazole is mediated mainly by cytochrome P450 2C19 (CYP2C19) with only a minor contribution of CYP3A4 and others. 6) CYP2C19, often referred to as S-mephenytoin 4Ј-hydroxylase, shows genetically determined polymorphism of enzyme activity with bimodal distributions. 7) In 1994, two mutant alleles, CYP2C19*2 and CYP2C19*3, were found in addition to a wild-type allele, CYP2C19*1, and six different genotypic patterns were theoretically defined. [8][9][10] In our previous studies, the pharmacokinetics of omeprazole and gastric pH after omeprazole administration in healthy subjects were also defined by bimodal distribution, and two groups were genetically assigned based on CYP2C19 genotypes: extensive metabolizers and poor metabolizers. 11,12) In anti-H. pylori therapy using omeprazole (20 mgϫ2/d for 1 week), amoxicillin (500 mgϫ4/d for 1 week), and clarithromycin (200 mgϫ4/d for 1 week), patients who were poor metabolizers all achieved eradication, while 17% of extensive metabolizers failed. 13,14) Several studies have shown that this therapeutic inefficacy might be overcome by high-dose omeprazole.1) Recently, Furuta et al. 15) empirically reported that an extra-high dose of omeprazole (40 mgϫ3/d) achieved eradication in an extensive metabolizer.In the present study, a single oral dose of omeprazole 20, 40, and 80 mg was administered to 7 healthy Japanese subjects with the CYP2C19 genotype. The recommended dose of omeprazole for extensive metabolizers was estimated in anti-H. pylori therapy based on pharmacokinetic considerations. MATERIALS AND METHODS ChemicalsOmeprazole and its two metabolites, 5Ј-hydroxyomeprazole and omeprazole sulfone, were obtained In anti-Helicobacter pylori therapy using omeprazole and antimicrobials, the efficacy can be related to the CYP2C19 genotype groups; the eradication rates were 83% in extensive metabolizers and 100% in poor metabolizers. The present study was undertaken to help predict the optimal dosage of omeprazole for extensive metabolizers in this therapy. Seven healthy Japanese subjects, classified based on the CYP2C19 genotype into extensive metabolizers (n‫)4؍‬ and poor metabolizers (n‫,)3؍‬ participated in this study. Each subject received a single oral dose of omeprazole 20, 40, and 80 mg, with at least a 1-week washout period between each dose. Plasma concentrations of omeprazole and its two metabolites were monitored for...

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Interphenotype differences in disposition and effect on gastrin levels of omeprazole—suitability of omeprazole as a probe for CYP2C19.

Cited by 173 publications

References 30 publications

Influence of the Meal and Genotype of CYP2C19 on the Pharmacokinetics of Proton Pump Inhibitors in Healthy Japanese Subjects

Influence of the Meal and Genotype of CYP2C19 on the Pharmacokinetics of Proton Pump Inhibitors in Healthy Japanese Subjects

Use of a cocktail probe to assess potential drug interactions with cytochrome P450 after administration of belatacept, a costimulatory immunomodulator

Optimal Dose of Omeprazole for CYP2C19 Extensive Metabolizers in Anti-Helicobacter pylori Therapy: Pharmacokinetic Considerations.

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