Search for the molecular basis of ultra-rapid CYP2C9-catalysed metabolism: relationship between SNP IVS8-109A&gt;T and the losartan metabolism phenotype in Swedes

Hatta, Fazleen Haslinda Mohd; Teh, Lay Kek; Helldén, Anders; Hellgren, Karin; Roh, Hyung‐Keun; Salleh, Mohd Zaki; Aklillu, Eleni

doi:10.1007/s00228-012-1210-0

Cited by 15 publications

(11 citation statements)

References 28 publications

(42 reference statements)

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“…These preliminary results suggest that the CYP2C9 IVS8-109 T allele could be related to a reduced CYP2C9 enzymatic activity on PHT. Our findings are supported by previous data reported by Hatta et al,12 who showed that the CYP2C9 IVS8-109 T allele was associated with 49,50 and/or ultra-rapid metabolizers. 17,19 At least some of these discrepancies may be due to alternate routes of clearance between different CYP2C19 drug substrates.…”

Section: Discussionsupporting

confidence: 95%

“…11 On the other hand, the CYP2C9 intronic single nucleotide polymorphism (SNP) IVS8-109 A4T has been associated with a lower activity of CYP2C9 on losartan in healthy Swedes. 12 In contrast, this variant showed an increased enzymatic activity on losartan in healthy volunteers from an Ecuadorian population. 13 For CYP2C19, more than 30 reduced or null function allelic variants have been identified (http://www.…”

Section: Introductionmentioning

confidence: 87%

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CYP2C9, CYP2C19, ABCB1 genetic polymorphisms and phenytoin plasma concentrations in Mexican-Mestizo patients with epilepsy

et al. 2015

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We aimed to explore the possible influence of CYP2C9 (*2, *3 and IVS8-109 A>T), CYP2C19 (*2, *3 and *17) and ABCB1 (1236C>T, 2677G>A/T and 3435C>T) on phenytoin (PHT) plasma concentrations in 64 Mexican Mestizo (MM) patients with epilepsy currently treated with PHT in mono- (n=25) and polytherapy (n=39). Genotype and allele frequencies of these variants were also estimated in 300 MM healthy volunteers. Linear regression models were used to assess associations between the dependent variables (PHT plasma concentration and dose-corrected PHT concentration) with independent variables (CYP2C9, CYP2C19 and ABCB1 genotypes, ABCB1 haplotypes, age, sex, weight, and polytherapy). In multivariate models, CYP2C9 IVS8-109 T was significantly associated with higher PHT plasma concentrations (t(64)=2.27; P=0.03). Moreover, this allele was more frequent in the supratherapeutic group as compared with the subtherapeutic group (0.13 versus 0.03, respectively; P=0.05, Fisher's exact test). Results suggest that CYP2C9 IVS8-109 T allele may decrease CYP2C9 enzymatic activity on PHT. More research is needed to confirm findings.

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Section: Discussionsupporting

confidence: 95%

Section: Introductionmentioning

confidence: 87%

CYP2C9, CYP2C19, ABCB1 genetic polymorphisms and phenytoin plasma concentrations in Mexican-Mestizo patients with epilepsy

et al. 2015

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“…The Swedes were not screened for CYP2C9*13 as it is mainly reported in Asian populations. Previously we found a significant relationship between an intronic SNP IVS8-109A > T with a lower CYP2C9 activity in Swedes (Hatta et al, 2012). In the present study, we extended the investigation by screening for this mutation in individuals with CYP2C9 alleles *2 and *3.…”

Section: Comparison Of Cyp2c9 Genotypes Between Swedes and Koreansmentioning

confidence: 71%

Differences inCYP2C9Genotype and Enzyme Activity Between Swedes and Koreans of Relevance for Personalized Medicine: Role of Ethnicity, Genotype, Smoking, Age, and Sex

Hatta

Lundblad

Ramsjö

et al. 2015

OMICS: A Journal of Integrative Biology

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Global personalized medicine demands the characterization of person-to-person and between-population differences in drug pharmacokinetics and pharmacodynamics. CYP2C9 pharmacokinetic pathway is subject to modulation by both genetic and environmental factors. CYP2C9 genotype-based dose recommendations (e.g., for warfarin) is advocated. However, the overall contribution of genotype for variation in enzyme activity may differ between populations. We evaluated the importance of ethnicity, genotype, smoking, body weight, age, and sex for CYP2C9 enzyme activity. CYP2C9 genotype and phenotype was determined in 148 Swedes and 146 Koreans using losartan as a probe. CYP2C9 enzyme activity was assessed using urinary losartan/metabolite E-3174 ratio. The frequency of CYP2C9 defective variant alleles (*2 and *3) was significantly higher in Swedes (10.8% and 12.5%) than in Koreans (0% and 5.8%). In matched genotypes, CYP2C9 enzyme activity was significantly lower in Swedes compared to Koreans (p<0.0001). In a univariate analysis, age, weight, ethnicity, genotype, and smoking were significant predictors of CYP2C9 phenotype. A stepwise multivariate analysis indicated ethnicity, genotype, and smoking remained as significant predictors of CYP2C9 enzyme activity, accounting for 50% of the total variance. In both study populations, CYP2C9 genotype was a significant predictor of CYP2C9 enzyme activity, but its contribution in explaining the total variance was lower in Koreans (26.6%) than Swedes (40%). In conclusion, we report significantly lower CYP2C9 enzyme activity in Swedes compared to Koreans, partly but not exclusively due to CYP2C9 pharmacogenetic variations. Ethnicity and environment factors need to be considered together with genotype for population-specific dose optimization and global personalized medicine.

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“…Extensive metabolizer frequencies and those of the more recently described ultrarapid metabolizers of CYP2C9 are also unknown [7]. It would be of great interest to genotype and phenotype a wide population sample in several geographical areas due to the large number of native groups in our country.…”

mentioning

confidence: 99%

Present status and perspective of pharmacogenetics in Mexico

Cuautle‐Rodríguez¹,

LLerena²,

Molina-Güarneros

2013

Drug Metabolism and Drug Interactions

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Drug costs account for up to 24% of the country's health expenditure and there are 13,000 registered drugs being prescribed. Diabetes is the main cause of death in the country, with over 85% of diabetic patients currently under drug treatment. The importance of knowing interindividual variability in drug metabolism on Mexican populations is thus evident. The purpose of this article is to provide an overlook of the current situation of pharmacogenetic research in Mexico, focusing on drug-metabolizing enzymes, and the possibility of developing a phenotyping cocktail for Mexican populations. So far, 21 pharmacogenetic studies on Mexican population samples (Mestizos and Amerindian) have been published. These have reported interindividual variability through phenotyping and/or genotyping cytochromes: CYP2D6, 2C19, 2C9, 2E1, and phase II enzymes UGT and NAT2. Some cytochromes with important clinical implications have not yet been phenotyped in Mexican populations. The development of a cocktail adapted to them could be a significant contribution to a larger knowledge on drug response variability at a lower price and shorter time. There are validated phenotyping cocktails that present several practical advantages, being valuable, safe, and inexpensive tools in drug metabolism characterization, which require only a single experiment to provide information on several cytochrome activities.

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Search for the molecular basis of ultra-rapid CYP2C9-catalysed metabolism: relationship between SNP IVS8-109A>T and the losartan metabolism phenotype in Swedes

Cited by 15 publications

References 28 publications

CYP2C9, CYP2C19, ABCB1 genetic polymorphisms and phenytoin plasma concentrations in Mexican-Mestizo patients with epilepsy

CYP2C9, CYP2C19, ABCB1 genetic polymorphisms and phenytoin plasma concentrations in Mexican-Mestizo patients with epilepsy

Differences inCYP2C9Genotype and Enzyme Activity Between Swedes and Koreans of Relevance for Personalized Medicine: Role of Ethnicity, Genotype, Smoking, Age, and Sex

Present status and perspective of pharmacogenetics in Mexico

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