Trial reportEuropean journal of clinical pharmacology2006
Effects of clarithromycin and verapamil on rabeprazole pharmacokinetics between CYP2C19 genotypes.
Trial report in European journal of clinical pharmacology, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 17 citations in OpenAlex.
- Pharmacokinetic interactions between ilaprazole and clarithromycin following ilaprazole, clarithromycin and amoxicillin triple therapy.Acta pharmacologica Sinica · 2012Trial
- Identification of the time-point which gives a plasma rabeprazole concentration that adequately reflects the area under the concentration-time curve.European journal of clinical pharmacology · 2006Trial
- In vivo quantitative prediction of the effect of gene polymorphisms and drug interactions on drug exposure for CYP2C19 substrates.The AAPS journal · 2013Article
- Importance of multi-p450 inhibition in drug-drug interactions: evaluation of incidence, inhibition magnitude, and prediction from in vitro data.Chemical research in toxicology · 2012Review
- Pharmacokinetic drug interactions of antimicrobial drugs: a systematic review on oxazolidinones, rifamycines, macrolides, fluoroquinolones, and Beta-lactams.Pharmaceutics · 2011Article
- Drug-drug interaction profiles of proton pump inhibitors.Clinical pharmacokinetics · 2010Review
- Rabeprazole: a review of its use in the management of gastric acid-related diseases in adults.Drugs · 2009Review
- Proton pump inhibitors: an update of their clinical use and pharmacokinetics.European journal of clinical pharmacology · 2008Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveRabeprazole as a proton pump inhibitor (PPI) is mainly reduced to rabeprazole thioether via a nonenzymatic pathway, with minor CYP2C19 and CYP3A4 involvement. The aim of this study was to compare possible effects of clarithromycin and verapamil as inhibitors of CYP3A4 on the pharmacokinetics of rabeprazole among CYP2C19 genotypes.
methodsA three-way randomized, double-blind, placebo-controlled crossover study was performed. Nineteen volunteers, of whom six were homozygous extensive metabolizers (EMs), eight were heterozygous EMs, and five were poor metabolizers (PMs) for CYP2C19, received three 6-day courses of either daily 800 mg clarithromycin, 240 mg verapamil, or placebo in a randomized fashion, with a single oral dose of 20 mg rabeprazole on day 6 in all cases. Plasma concentrations of rabeprazole and rabeprazole thioether were monitored up to 24 h after the dosing.
resultsIn the control phase, the AUC(0-infinity) values for rabeprazole and rabeprazole thioether were 1,005+/-366 and 412+/-149 ng.h/ml in homozygous EMs, 1,108+/-340 and 491+/-245 ng.h/ml in heterozygous EMs, and 2,697+/-364 and 2,116+/-373 ng.h/ml in PMs, respectively. There were significant differences (p<0.001) in the AUC(0-infinity) of rabeprazole and rabeprazole thioether among three different CYP2C19 genotypes. In the clarithromycin and verapamil phases, no significant differences were found in the pharmacokinetic parameters of rabeprazole compared with those in the control phase irrespective of CYP2C19 genotypes, whereas the AUC(0-infinity) of rabeprazole thioether was significantly increased 2.8-fold and 2.3-fold in homozygous EMs (p<0.01), 2.0-fold and 2.0-fold in heterozygous EMs (p<0.05), and 1.6-fold and 1.9-fold in PMs (p<0.05), respectively. In each genotype group for CYP2C19, there were no statistical differences in the percent increase in those pharmacokinetic parameters between the clarithromycin and verapamil pretreatment phases.
conclusionThe pharmacokinetic parameters of rabeprazole were not altered by clarithromycin or verapamil irrespective of the CYP2C19 genotypes. However, this result shows that both clarithromycin and verapamil significantly influence the disposition of rabeprazole by inhibiting the oxidation of the thioether, since the AUC(0-infinity) of rabeprazole thioether that has no effect on acid secretion increased. Therefore, the pharmacokinetic interactions between rabeprazole and CYP3A4 or P-glycoprotein inhibitors have limited clinical significance.
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