Effect of co-administered inducer or inhibitor on omeprazole pharmacokinetics based on CYP2C19 genotype

Kamiya, Chiaki; Inui, Naoki; Hakamata, Akio; Miyakawa, Sachiko; Tanaka, Shimako; Uchida, Shinya; Namiki, Noriyuki; Odagiri, Keiichi; Watanabe, Hiroshi

doi:10.1016/j.jphs.2019.03.001

Cited by 14 publications

(12 citation statements)

References 24 publications

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“…To further validate microdosed intravenous omeprazole as a probe drug, we also assessed the effect of CYP2C19 inhibition by loading doses of voriconazole. As expected, 29 the extent of the interaction depended on the CYP2C19 genotype with no relevant change in PMs and a substantial omeprazole exposure increase in EMs. More specifically, voriconazole led to an anticipated increase of omeprazole drug exposure in CYP2C19 EMs, 13 whereas metabolic clearance and plasma drug concentration of 5-OH omeprazole were reduced.…”

Section: Discussionsupporting

confidence: 79%

Application of Microdosed Intravenous Omeprazole to Determine Hepatic CYP2C19 Activity

Mahmoudi

Foerster

Burhenne

et al. 2020

The Journal of Clinical Pharma

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Omeprazole is an established probe drug to assess cytochrome P450 (CYP) 2C19 activity (phenotyping). Because it has nonlinear pharmacokinetics (PK) after oral administration (autoinhibition of metabolism), the true impact of coadministered perpetrators on CYP2C19 substrates might be underestimated after regular doses. We tested the dose linearity of an intravenous omeprazole microdose of 100 μg and compared it with a 20-mg dose in 4 healthy poor metabolizers (PMs) and 6 extensive metabolizers (EMs) of CYP2C19 in the presence and absence of a strong inhibitor (voriconazole). Without voriconazole, omeprazole exposure was dose-proportional irrespective of the genotype, but in PMs geometric mean ratios (GMRs) of AUC 0-∞ were 6.6-fold higher and molar metabolic ratios of 5-OH omeprazole/omeprazole approximately 10-fold lower. Voriconazole increased omeprazole exposure in EMs approximately 5-fold (AUC 0-4 GMR after 100 μg omeprazole, 4.61; 90% confidence interval [CI], 2.69-7.89; AUC 0-4 GMR after 20 mg omeprazole, 5.5; 90%CI, 1.07-1.46), whereas no clinically significant impact on PK in PMs was observed (GMR AUC 0-4 after 100 μg omeprazole, 1.29; 90%CI, 0.81-2.04; GMR AUC 0-4 after 20 mg omeprazole, 1.25; 90%CI, 1.07-1.46). Linear regression and Bland-Altman analyses revealed excellent agreement between AUC 0-∞ and AUC 0-4 of omeprazole (r 2 = 0.987; bias, 0.35%; 95%CI, −3.197% to 3.89%) and also the molar metabolic ratio, 5-OH omeprazole/omeprazole (r 2 = 0.987; bias, −3.939; 95%CI, −9.06% to −1.18%), suggesting that an abbreviated sampling protocol can be used for intravenous CYP2C19 phenotyping and drug interaction studies. In conclusion, the PK of intravenous omeprazole microdoses closely reflects the changes observed with regular omeprazole doses; however, to avoid autoinhibition of probe drugs, microdosing appears to be the favorable technique.

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Section: Discussionsupporting

confidence: 79%

Application of Microdosed Intravenous Omeprazole to Determine Hepatic CYP2C19 Activity

Mahmoudi

Foerster

Burhenne

et al. 2020

The Journal of Clinical Pharma

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“…Peptic ulcer is a common condition caused by environmental factors (consumption of spicy food, alcohol abuse, coffee, smoking, stress) [17,38,48], non-compliance with meal times, co-infection with Helicobacter pylori, as well as the abuse of drugs involved in iatrogenic aggression on the gastric mucosa (nonsteroidal anti-inflammatory drugs -NSAIDs, corticosteroids, etc.). The treatment relies on therapeutic classes such as proton pump inhibitors, antihistamines blocking H2 receptors which have anti-secretory action and can cause drug interactions (inhibition of CYP2C9, 2C19 for omeprazole, CYP3A4 for certain antihistamines H2 drugs) [25,26]. Drugs with protective action on the gastric layer are used rather infrequently (prostaglandin analogues, carbenoxolone, sucralfate).…”

Section: Introductionmentioning

confidence: 99%

Study of the Potential Antiulcerous Action of Hydroalcoholic Extracts From Prunella Vulgaris L. Of Romanian Origin

Groşan¹

2020

FARMACIA

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Prunella vulgaris L. (Lamiaceae family) species is widespread throughout the world and the fruit-spike is used in folk medicine in many countries. The Romanian resource of Prunellae spica is poorly studied from a phytochemical and pharmacological point of view; accordingly, the present study aimed to evaluate the anti-ulcer action of a hydroalcoholic extract of this species with standardized polyphenol content. The extracts used were phytochemically characterized by the total polyphenol content (TPC) and by the determination of the constituents (phenol-carboxylic acids, flavonoids) by HPLC-MS/MS. Quantitative analysis showed the presence of flavonoids in glycosidic form in fairly large quantities (hyperoside, rutoside, isoquercitrin); on the other hand, smaller quantities of aglycones (quercetol, kaempferol, apigenin) were identified and quantified. Moreover, phenolcarboxylic acids, such as caftaric, ferulic, p-coumaric acid, were measured. Two types of doses (high dose-50 mg/kg body weight (kgbw), respectively low dose 10 mg/ kgbw, values expressed in gallic acid equivalents) were administered preventively/curatively in rats with phenylbutazone-induced ulcer; ranitidine at 50 mg/kgbw was used as an activity control. Efficacy was quantified by measuring ulcer index, as well as by examination of gross features and histopathological changes. The hydroalcoholic extracts of Prunella vulgaris L. proved to have a dose-dependent antiulcerous action in curative treatment. As the titratable acidity is not decreased by the treatment, the effect is mediated by the prevention of oxidative inflammation of the mucosa. Histopathological results confirmed these in vivo results. Prunellae spica of Romanian origin is a plant resource rich in polyphenols that has shown protective effects on nonsteroidal anti-inflammatory drugs (NSAID)-related gastric ulcer. The observed effects are dose-dependent, probably mediated by inhibition of oxidative stress in the mucosa and promotion of regeneration processes. Rezumat Specia Prunella vulgaris L. (Lamiaceae) este răspândită în întreaga lume, iar fructul este folosit în medicina populară în multe țări. Resursa românească de Prunellae spica este puțin studiată din punct de vedere fitochimic și farmacologic, în consecință, prezentul studiu a avut ca scop evaluarea acțiunii anti-ulceroase a unui extract hidroalcoolic din această specie cu conținut standardizat de polifenoli. Extractele utilizate au fost caracterizate fitochimic prin conținutul total de polifenoli (TPC) și prin determinarea constituenților (acizi fenol-carboxilici, flavonoizi) prin HPLC-MS/MS. Analiza cantitativă a arătat prezența flavonoidelor în formă glicozidică în cantități mari (hiperozid, rutozid, izoquercitrin), pe de altă parte, au fost identificate și cuantificate cantități mai mici de agliconi (quercetol, kaempferol, apigenină). Mai mult, au fost cuantificați acizii fenol-carboxilici, ca acidul caftaric, ferulic, p-cumaric. Două tipuri de doze (doză mare-50 mg/kgc, respectiv doză mică 10 mg/kgc, valori exprimate în ech...

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“…23,28 Previous clinical DDI studies indicated that inhibition of CYP2C8 by gemfibrozil occurs within 1 hour after oral administration, with the effect persisting for at least 48 hours after drug discontinuation. 29,30 In the current study, concomitant administration of clopidogrel with selexipag significantly increased AUC 0-∞ of ACT- 31 Axelsen et al assessed the effect of the CYP2C8 genotype on DDIs between selexipag and clopidogrel. They found that the effect of clopidogrel on ACT-333679 was higher in the *1/*3 group than in the wild type group.…”

Section: Discussionmentioning

confidence: 69%

“…Second, we did not assess CYP2C8 polymorphisms in our participants. Polymorphisms of CYP enzymes have great effects on their enzymatic activities and the impact of CYP inhibitors 31 . Axelsen et al .…”

Section: Discussionmentioning

confidence: 99%

Clinical evaluation of drug–drug interactions between the cytochrome P450 substrates selexipag and clopidogrel in Japanese volunteers

Katayama

Odagiri

Hakamata

et al. 2020

Brit J Clinical Pharma

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The strong cytochrome P450 (CYP) 2C8 inhibitor gemfibrozil has been demonstrated to increase the area under the plasma concentration-time curve from 0 to infinity (AUC 0-∞) of ACT-333679, an active metabolite of selexipag, by 11-fold. Similarly to gemfibrozil, the CYP2C8 inhibitor clopidogrel increased ACT-333679 concentration by 1.9-fold after a single loading dose (300 mg once daily) and 2.7-fold after repeated treatment with the maintenance dose (75 mg once daily) in Europeans. However, the effects of clopidogrel on the pharmacokinetics of selexipag and ACT-333679 have not been fully elucidated in the Japanese population. Methods: We investigated the effect of clopidogrel on the pharmacokinetics of selexipag and ACT-333679 in 14 healthy Japanese volunteers. Results: The concomitant administration of clopidogrel with selexipag did not influence the maximum concentration and AUC 0-∞ of selexipag, whereas it significantly increased AUC 0-∞ of ACT-333679 by approximately 1.90-fold (90% confidence interval 1.69-2.14) without changing the maximum concentration. When selexipag was administered 1 day after clopidogrel was discontinued, the increase in AUC 0-∞ of ACT-333679 was 1.37-fold (90% confidence interval 0.93-2.02), suggesting that, although the inhibitory effect of clopidogrel on CYP2C8 was reduced, it persisted for at least 1 day after withdrawal. Conclusion: Our results demonstrated the impact of clopidogrel on the pharmacokinetics of selexipag and its active metabolite and suggested that selexipag should be carefully prescribed with clopidogrel with dose adjustment or reducing the dosing frequency in Japanese clinical settings.

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Effect of co-administered inducer or inhibitor on omeprazole pharmacokinetics based on CYP2C19 genotype

Cited by 14 publications

References 24 publications

Application of Microdosed Intravenous Omeprazole to Determine Hepatic CYP2C19 Activity

Application of Microdosed Intravenous Omeprazole to Determine Hepatic CYP2C19 Activity

Study of the Potential Antiulcerous Action of Hydroalcoholic Extracts From Prunella Vulgaris L. Of Romanian Origin

Clinical evaluation of drug–drug interactions between the cytochrome P450 substrates selexipag and clopidogrel in Japanese volunteers

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