The activation of the biguanide antimalarial proguanil co‐segregates with the mephenytoin oxidation polymorphism‐a panel study.

Ward, SA; Helsby, Nuala A.; Skjelbo, Erik; Brøsen, Kim; Gram, Lennart; Breckenridge, AM

doi:10.1111/j.1365-2125.1991.tb05594.x

Cited by 146 publications

(74 citation statements)

References 24 publications

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“…Subsequent studies confirmed that S-mephenytoin hydroxylase is polymorphically expressed (Kupfer and Preisig, 1984;Wedlund et al, 1984) and that other drugs such as omeprazole and proguanil have metabolism that cosegregates with that of mephenytoin (Table 5) (Ward et al, 1991;Chang et al, 1995a). The ability of individuals to metabolize S-mephenytoin has enabled them to be classified as PMs or EMs.…”

Section: Cyp2c19mentioning

confidence: 87%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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Section: Cyp2c19mentioning

confidence: 87%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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“…Keywords CYP2C19, omeprazole, gender, Korean, Swedes [2] , proguanil [3] and proton pump inhibitors (PPIs) [4]. The major metabolites of omeprazole detected in vivo in human plasma are 5-hydroxyomeprazole formed by CYP2C19 and omeprazole sulphone formed by CYP3A4 [5,6].…”

Section: Discussionmentioning

confidence: 99%

CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking

Ramsjö

Aklillu

Bohman

et al. 2010

Eur J Clin Pharmacol

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Objectives To compare CYP2C19 enzyme activity between Swedes and Koreans controlling for the effect of CYP2C19 genotype, sex, oral contraceptive use and smoking habit.Methods CYP2C19 activity was determined in 185 healthy Swedish and 150 Korean subjects as omeprazole/5-hydroxyomeprazole ratio (metabolic ratio; MR) using high-performance liquid chromatography. Genotyping was performed by PCR using Taqman assay.Results As expected, a higher incidence of poor metabolizers (PM) was found in Koreans (14%) compared to Swedes (3.8%) and the frequency of the CYP2C19*17 allele was very low in Koreans 0.3%. Among subjects homozygous for CYP2C19*1, Koreans displayed significantly lower CYP2C19 enzyme activity than Swedes (p<0.000001). Interestingly in Koreans a pronounced gender difference was apparent: females (n=24) had significantly lower MR than males (N=30) (p<0.0001) but such a gender difference was not seen among Swedes. Swedish OC users had a higher MR than non-users (p<0.00001), whereas OC was only used by one Korean. No effect of smoking was observed. ConclusionsWe find specific gender dependent effects of CYP2C19 activity in Koreans but not in Swedes. Controlling for the effect of genotype and sex, Koreans display lower CYP2C19 activity than Swedes. The genetic, epigenetic or environmental basis for this difference remains to be identified.

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“…The assay had a lower limit of detection of 5 and 3 ng ml -1 and an inter-and intra-assay variability of <6% for proguanil and the metabolite cycloguanil, respectively. A proguanil : cycloguanil metabolic ratio of >10 corresponds to the PM phenotype [4].…”

Section: Methodsmentioning

confidence: 99%

“…CYP2C19 activity status was determined using the probe drug proguanil (200 mg) [4]. The metabolic ratio was calculated from the plasma concentrations of proguanil and its metabolite cycloguanil by HPLC analysis of a 3 h blood sample.…”

Section: Methodsmentioning

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 activation of the biguanide antimalarial proguanil co‐segregates with the mephenytoin oxidation polymorphism‐a panel study.

Cited by 146 publications

References 24 publications

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking

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

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