Impact of the CYP2C19*17 Allele on the Pharmacokinetics of Omeprazole and Pantoprazole in Children: Evidence for a Differential Effect

Abstract

ABSTRACT:The impact of the CYP2C19*17 allele on the pharmacokinetics of pantoprazole and omeprazole in previously studied children (n ‫؍‬ 40) was explored. When pantoprazole area under the plasma concentration versus time curve (AUC) was examined as a function of CYP2C19 genotype, a significantly lower AUC was observed for subjects identified as CYP2C19*1/*1 and *1/*17. For pantoprazole, a statistically significant relationship was observed between CYP2C19 genotype and both dose-corrected AUC (p < 0.0001) and the apparent elimination rate constant (K el ; p ‫؍‬ 0.0012); no significant genotype-phenotype relationships were observed for omeprazole. CYP2C19*17 is characterized by Ϫ806CϾT (rs12248560) in the regulatory gene region and increases transcription levels. Subjects carrying CYP2C19*17 have higher CYP2C19 activity toward mephenytoin and omeprazole (Sim et al., 2006). There is limited information regarding the effect of CYP2C19*17 on the pharmacokinetics of CYP2C19 substrates in adults (Rudberg et al., 2008), and only a single study assessed the clinical outcome (Kurzawski et al., 2006). The goals of this exploratory study were as follows: 1) to characterize the effect of CYP2C19 genotype, especially the CYP2C19*17 allele, on the pharmacokinetics of two proton pump inhibitors (PPIs), omeprazole and pantoprazole, in a pediatric cohort and 2) to determine the frequency of CYP2C19*17 in population samples that represented different ethnic backgrounds. Materials and MethodsClinical Trials. The current investigation was enabled by a reassessment of data and samples available from previous pharmacokinetic studies of omeprazole (Kearns et al., 2003b) and pantoprazole (Kearns et al., 2008) conducted in pediatric populations for the purpose of product labeling. The Institutional Review Boards at participating institutions approved both investigations, and subjects were enrolled by parental permission and patient assent, as appropriate. The approvals contained provisions for data reanalysis and expanded genotype analysis of stored DNA specimens. Study designs, complete methods, and results were previously described in detail (Kearns et al., 2003b(Kearns et al., , 2008, and therefore only pertinent information is recapitulated in this brief communication.The omeprazole study comprised 37 subjects, 23 of whom yielded evaluable pharmacokinetic data (Kearns et al., 2003b); these subjects were further investigated for CYP2C19*17. Ten or 20 mg of omeprazole was administered as a single solid oral dose to subjects aged 9.5 Ϯ 3.8 years (mean Ϯ S.D.; range, 2-16 years) and weighing 26.2 Ϯ 15.1 kg (range, 11-75 kg), and 10 participants were male.The pantoprazole study (Kearns et al., 2008) reported two cohorts of children, an oral and an intravenous study arm. The orally dosed cohort consisted of 24 subjects (16 male) aged 10.8 Ϯ 3.4 years (range, 5-16 years) and weighing 45.0 Ϯ 19.9 kg (range, 20 -90 kg). Subjects received a single oral dose of 20 or 40 mg of pantoprazole. DNA was available for all 24 subjects. The intravenous...

Increased Hospital Stay and Allograft Disfunction in Renal Transplant Recipients with Cyp2c19 AA Variant in SNP rs4244285

“…Even in homozygotes, any observed ultrafast metabolic profiles have been within the range seen in the wild-type homozygotes. In addition, other authors have reported (Kearns et al, 2010) that, although for pantoprazole, a statistically significant relationship was observed between CYP2C19*17 and both dosecorrected areas under the curve and the apparent elimination rate constant, no significant genotype-phenotype relationships were observed for omeprazole. Unfortunately, CYP2C19*17 was not initially included in the study, and we cannot contribute to clarify how it influences the observed effects.…”

Developmental Changes in P-Glycoprotein Function in the Blood–Brain Barrier of Nonhuman Primates: PET Study with R-11C-Verapamil and 11C-Oseltamivir

“…Some drugmetabolizing enzymes display ontogeny (2,3) in humans, but the ontogeny of drug transporters has been described only in murine models.…”

Evaluation of Predictive Cyp2C19 Genotyping Assays Relative to Measured Phenotype in a South African Cohort

“…In the study by Ramsjö et al [38], it was reported that the cut-off in Koreans was as high as -3.04, while it was a low -0.86 17 in a Swedish cohort. The cut-off value separating the PM and IM phenotypes in this study was -1.152, which is within the range of cut-off values previously reported.…”

“…Plasma concentrations of omeprazole sulphone, a CYP3A4 metabolite, could have been measured to evaluate if this was indeed the case, but this was not within the scope of the project. Kearns et al [17] highlight this dilemma and suggest pantoprazole (also a proton pump inhibitor) as a more selective probe drug for CYP2C19 phenotypic analysis. Metabolism of escitalopram, an antidepressant and selective serotonin reuptake inhibitor, has also been shown to not be influenced by CYP2C19*17, and is hence another example of where metabolism predictions may be substrate specific [16].…”

“…3 Genetic variation in CYP2C19 (OMIM 124020) has been associated with variable responses to numerous drugs including clopidogrel (anticoagulant), citalopram (and many other antidepressants), proguanil (prophylactic anti-malarial) and omeprazole (and other proton pump inhibitors) [6][7][8][9][10][11][12] The non-functional CYP2C19*2 and *3 alleles are the most commonly genotyped and have been prioritised in many CYP2C19 studies [13]. Responsible for increased CYP2C19 expression, CYP2C19*17 is important for the prediction of UMs and has been found to be relatively frequent in certain populations [14][15][16][17][18][19]. The above-mentioned alleles have been prioritised based on observations in cohorts of predominantly European and Asian descent.…”