Eriko Shikata

Tottori University, TTJ, Tottori, Japan

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Publications (4)19.1 Total impact

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    ABSTRACT: Considerable interindividual variabilities in clinical efficacy and adverse events are sometimes recognized in the treatment of Type 2 diabetes mellitus with oral antihyperglycemic drugs. Metformin is the most commonly used biguanide in clinical practice, and also improves insulin resistance and reduces cardiovascular risk. However, certain patients taking metformin do not respond sufficiently. The molecular reasons for the variability in response to metformin are not clear. However, it has been recently suggested that genetic factors may be responsible for the variability. Metformin is not metabolized but is transported by at least two organic cation transporters (OCT), OCT1 and OCT2. Recently, genetic polymorphisms in OCT 1 and OCT2 have been found to be associated with changes in pharmacokinetic/pharmacodynamic responses to substrate drugs. This review focuses on the impact of the genetic polymorphism of organic cation transporters on transport activity, and the implications for the clinical efficacy of metformin.
    No preview · Article · May 2008 · Pharmacogenomics
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    ABSTRACT: Organic cation transporters (OCTs) are responsible for the hepatic and renal transport of metformin. In this study we analyzed variants of OCT1 and OCT2 genes in 33 patients (24 responders and nine non-responders) based on the hypothesis that polymorphisms in both genes contribute to large inter-patient variability in the clinical efficacy of metformin. The sequences of the 5'-flanking and coding regions of the two genes of interest were screened by single-strand conformation polymorphism (SSCP) analysis. To compare the causative factors between responders and non-responders, we performed stepwise discriminant functional analysis. Age, body mass index (BMI) and treatment with lipid-lowering agents were demonstrated as positive predictors, and two mutations in the OCT1 gene, -43T > G in intron 1 and 408Met > Val (1222A > G) in exon 7, were negative and positive predictors, respectively, for the efficacy of metformin; the predictive accuracy was 55.5% (P < 0.05). Subsequent study indicated that OCT1 mRNA levels tended to be lower in human livers with the 408Met (1222A) variant, though the differences did not reach the level of significance. In this study it is suggested that OCT1 and OCT2 gene polymorphisms have little contribution to the clinical efficacy of metformin.
    Preview · Article · Jan 2007 · Journal of Human Genetics

  • No preview · Article · Nov 2006 · European Journal of Clinical Pharmacology
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    ABSTRACT: We analyzed mutations of 7 vitamin K-dependent protein and cytochrome P450 2C9 genes in 45 patients and investigated whether any contribute to the large interpatient variability in the warfarin dose-effect relationship. Total clearance and daily dose, INR and INR/Cp, were used as pharmacokinetic and pharmacodynamic indexes, respectively. Patients were grouped by genotype based on a single polymorphism and combinations of polymorphisms. Among the 30 sequence variants identified, CYP2C9*3, 165Thr-->Met of the factor II gene, -402G-->A, (37-bp repeat)n, and -746T-->C of the factor VII gene, and (CAA repeat)n of the gamma-glutamyl carboxylase gene were selected as candidate polymorphisms. As the analysis of single polymorphisms implied, the highest INR/Cp mean values and the lowest warfarin maintenance doses were observed in patients homozygous for the 165Met, -402G, (37-bp repeat)6 and -746T alleles. Multiple regression analysis revealed that warfarin sensitivity was independently associated with -402G-->A, (CAA repeat)n, CYP2C9*3, and 165Thr-->Met, which accounted for 50% of variance. These results suggest that part of the considerable interpatient variation is attributable to genetic variation, and the combined genotyping of CYP2C9 and certain vitamin K-dependent protein genes is useful for predicting anticoagulant responses.
    Preview · Article · Apr 2004 · Blood