The Effect of Aging on the Relationship between the Cytochrome P450 2C19 Genotype and Omeprazole Pharmacokinetics

Ishizawa, Yukio; Yasui‐Furukori, Norio; Takahata, Takenori; Sasaki, Mutsuo; Tateishi, Tetsuya

doi:10.2165/00003088-200544110-00005

Cited by 61 publications

(41 citation statements)

References 32 publications

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“…The effect of age on enzyme activity has been reported for several major P450s such as CYP2C19, CYP2D6, and CYP3A4 in humans (Ishizawa et al 2005;Stevens 2006;Wauthier et al 2007;Stevens et al 2008). However, the lack of an age effect on these enzymes has also been indicated (Simon et al 2001;Gorski et al 2003;Parkinson et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver

Yang¹,

Zhang²,

Molony³

et al. 2010

Genome Res.

238

226

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Liver cytochrome P450s (P450s) play critical roles in drug metabolism, toxicology, and metabolic processes. Despite rapid progress in the understanding of these enzymes, a systematic investigation of the full spectrum of functionality of individual P450s, the interrelationship or networks connecting them, and the genetic control of each gene/enzyme is lacking. To this end, we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity. Several novel SNPs associated with CYP2D6 expression and enzyme activity were validated in an independent human cohort. By constructing a weighted coexpression network and a Bayesian regulatory network, we defined the human liver transcriptional network structure, uncovered subnetworks representative of the P450 regulatory system, and identified novel candidate regulatory genes, namely, EHHADH, SLC10A1, and AKR1D1. The P450 subnetworks were then validated using gene signatures responsive to ligands of known P450 regulators in mouse and rat. This systematic survey provides a comprehensive view of the functionality, genetic control, and interactions of P450s.

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Section: Discussionmentioning

confidence: 99%

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver

Yang¹,

Zhang²,

Molony³

et al. 2010

Genome Res.

238

226

View full text Add to dashboard Cite

show abstract

“…The clearance of drugs metabolized by CYP2C19 varies 5-to 20-fold among individuals and ethnic groups primarily because of effects of genetic polymorphisms (Goldstein, 2001;Desta et al, 2002), but also as a result of nongenetic factors, such as drug interactions (Desta et al, 2002), age (Ishizawa et al, 2005), pregnancy (McGready et al, 2003), and disease state (Desta et al, 2002;Frye et al, 2006). CYP2C19 is a clinically relevant drug-metabolizing enzyme for which genotyping and phenotyping information has the potential to improve drug safety and efficacy (Scott, 2011;Ventola, 2013a).…”

Section: Introductionmentioning

confidence: 99%

CYP2C19 Phenoconversion by Routinely Prescribed Proton Pump Inhibitors Omeprazole and Esomeprazole: Clinical Implications for Personalized Medicine

Klieber

Oberacher

Hofstaetter

et al. 2015

J Pharmacol Exp Ther

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The phenotype pantoprazole-13 C breath test (Ptz-BT) was used to evaluate the extent of phenoconversion of CYP2C19 enzyme activity caused by commonly prescribed proton pump inhibitors (PPI) omeprazole and esomprazole. The Ptz-BT was administered to 26 healthy volunteers and 8 stable cardiovascular patients twice at baseline and after 28 days of PPI therapy to evaluate reproducibility of the Ptz-BT and changes in CYP2C19 enzyme activity (phenoconversion) after PPI therapy. The average intrapatient interday variability in CYP2C19 phenotype (n 5 31) determined by Ptz-BT was considerably low (coefficient of variation, 17%). Phenotype conversion resulted in 25 of 26 (96%) nonpoor metabolizer (non-PM) volunteers/ patients as measured by the Ptz-BT at baseline and after PPI therapy. The incidence of PM status by phenotype following administration of omeprazole/esomeprazole (known inhibitors of CYP2C19) was 10-fold higher than those who are genetically PMs in the general population, which could have critical clinical implications for personalizing medications primarily metabolized by CYP2C19, such as clopidogrel, PPI, cyclophosphamide, thalidomide, citalopram, clonazepam, diazepam, phenytoin, etc. The Ptz-BT can rapidly (30 minutes) evaluate CYP2C19 phenotype and, more importantly, can identify patients with phenoconversion in CYP2C19 enzyme activity caused by nongenetic factors such as concomitant drugs.

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“…Co-morbidities such as liver disease or cancer alter the capacity of this enzyme, as do concurrent administration of drugs that are substrates for this enzyme. Another factor is advanced age, where omeprazole clearance is almost halved [3].Thus the phenotype may be controlled by age, co-morbidities, other medications and CYP2C19 genotype.…”

Section: Introductionmentioning

confidence: 99%

Omeprazole‐induced acute interstitial nephritis is not related to CYP2C19 genotype or CYP2C19 phenotype

Helsby¹,

Lo²,

Simpson³

et al. 2010

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Omeprazole‐induced acute interstitial nephritis (OIAIN) is a rare adverse drug reaction. It is typically considered to be an idiosyncratic reaction affecting elderly patients. Omeprazole is a substrate for CYP2C19 and individuals who are homozygous variant for the null allele are poor metabolizers of this drug. These individuals have higher exposure to omeprazole. In the elderly metabolism of omeprazole is reported to be decreased despite a ‘normal activity’ genotype. WHAT THIS PAPER ADDS • The CYP2C19 poor metabolizer genotype was not over represented in patients with OIAIN. However, almost a third of the patients appeared to have deficient CYP2C19 function. • Metabolism of omeprazole may be compromised in the elderly and caution should be exercised when using this medication in this group of patients. AIM Omeprazole‐induced acute interstitial nephritis (OIAIN) is a rare adverse event. It is unknown if this is an idiosyncratic immune mediated reaction or if it relates to direct drug toxicity. Individuals who are homozygous for the variant alleles of CYP2C19 are poor metabolizers of omeprazole and have a greater exposure to the drug. The aim of this study was to determine the prevalence of the CYP2C19 poor metabolizer genotype and phenotype in patients with OIAIN. METHODS Twenty patients were genotyped for the CYP2C19 variant alleles (*2, 681G>A and *3, 636G>A) by RFLP‐PCR analysis and eighteen phenotyped for CYP2C19 metabolizer status. RESULTS The frequency of the CYP2C19*2 allelic variant was 12.5%, no *3 allelic variants were detected and no patient was a homozygous variant genotype. This was not different from the expected frequency. 33% of subjects were phenotypically CYP2C19 poor metabolizers. CONCLUSIONS There was discordance between CYP2C19 genotype and phenotype. However, up to 45% of healthy elderly subjects have a poor metabolizer phenotype. Thus neither CYP2C19 poor metabolizer genotype nor phenotype is a risk factor for OIAIN.

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The Effect of Aging on the Relationship between the Cytochrome P450 2C19 Genotype and Omeprazole Pharmacokinetics

Cited by 61 publications

References 32 publications

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver

CYP2C19 Phenoconversion by Routinely Prescribed Proton Pump Inhibitors Omeprazole and Esomeprazole: Clinical Implications for Personalized Medicine

Omeprazole‐induced acute interstitial nephritis is not related to CYP2C19 genotype or CYP2C19 phenotype

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