Effect of CYP2C9 and VKORC1 genotypes on early-phase and steady-state warfarin dosing in Korean patients with mechanical heart valve replacement

Kim, Ho-Sook; Lee, Sang Seop; Oh, Minkyung; Jang, Yin-Jin; Kim, Eun Young; Han, I.; Cho, Kwang-Hyun; Shin, Jae‐Gook

doi:10.1097/fpc.0b013e32831a9ae3

Cited by 48 publications

(47 citation statements)

References 34 publications

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“…Its reported frequency is 0.003 in Europeans [13] and 0.002 to 0.004 in Asians [14, 15]. In vitro studies show that the CYP2C9*14 allele is associated with 80–90% lower catalytic activity toward tolbutamide and 8% of the wild-type activity against S -warfarin [6, 16].…”

Section: Discussionmentioning

confidence: 99%

Warfarin Dose Requirements in a Patient with the CYP2C914* Allele

et al. 2014

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We describe a 64-year-old male of Indian descent with a history of atrial fibrillation who was started on warfarin after hospital admission for acute stroke. He received genotype-guided warfarin dosing as per the standard-of-care at our hospital, with daily dose recommendations provided by the pharmacogenetics service. Genotyping revealed the rare CYP2C9*1/*14 genotype and warfarin insensitive VKORC1 -1639GG and CYP4F2 433Met/Met genotypes. The patient received an initial warfarin loading dose of 4 mg for 2 days, followed by 2–3 mg/day for the following 11 days. He reached a therapeutic international normalized ratio on day 5, which was maintained over the following week. This report adds to the limited data of the effects of the CYP2C9*14 allele on warfarin dose requirements.

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Section: Discussionmentioning

confidence: 99%

Warfarin Dose Requirements in a Patient with the CYP2C914* Allele

et al. 2014

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“…In addition, genotyping for CYP2C8*7 and *8 was performed by TaqMan assays in 400 Koreans according to the manufacturer's instructions (Applied Biosystems protocol PN 4332856D). Genotyping for the presence of CYP2C9*3, *13, and *14 in all phenotyped subjects was performed as described previously (Lee et al, 2005b;Kim et al, 2009).…”

Section: Methodsmentioning

confidence: 99%

Discovery of a Novel Allelic Variant of CYP2C8, *CYP2C8**11, in Asian Populations and Its Clinical Effect on the Rosiglitazone Disposition In Vivo

Yeo¹,

Lee²,

Lee³

et al. 2011

Drug Metab Dispos

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ABSTRACT:The objectives of this study were to identify the genetic variants of CYP2C8, analyze CYP2C8 single nucleotide polymorphisms (SNPs), and characterize their functional consequences in the CYP2C8 substrate drug rosiglitazone in humans. The direct full sequencing of CYP2C8 genomic DNA was performed in a Korean population (n ‫؍‬ 50). A total of 17 CYP2C8 variants including a novel coding variant (E274Stop) were identified. The novel CYP2C8 E274Stop variant was assigned as CYP2C8*11 by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee. Seventeen SNPs were used to characterize linkage disequilibrium, haplotype structures, and haplotype tagging SNPs. Genotyping for CYP2C8*11 in an extended set of Koreans (n ‫؍‬ 400), whites (n ‫؍‬ 100), Han Chinese (n ‫؍‬ 348), Vietnamese (n ‫؍‬ 100), and African Americans (n ‫؍‬ 93) was performed by a newly developed pyrosequencing method. The frequency of CYP2C8*11 was 0.3% in Koreans, 1% in Vietnamese, and 0.14% in Chinese. However, none of the whites or African Americans contained the CYP2C8*11 allele. Subjects with CYP2C8*1/*11 exhibited higher plasma concentration-time profiles of rosiglitazone than those of nine control subjects carrying CYP2C8*1/*1. The area under the concentrationtime curve and peak plasma concentration of rosiglitazone in individuals carrying CYP2C8*1/*11 (n ‫؍‬ 5) were 54 and 34% higher than the mean values observed in the control subjects carrying CYP2C8*1/*1 (P ‫؍‬ 0.015 and P ‫؍‬ 0.025, respectively). In summary, this is the first report to characterize the allele frequency and haplotype distribution of CYP2C8 in a Korean population, and it provides functional analysis of a new variant CYP2C8*11. Our findings suggest that individuals carrying CYP2C8*11, a null allele found in Asians only, may have lower activity for metabolizing CYP2C8 substrate drugs.

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“…41,42) Furthermore, it is recognized that CYP2C9*5, CYP2C9*8, CYP2C9*11, and CYP2C9*13 reduce the clearance of warfarin in humans. [42][43][44][45][46] However, there are still many unknown aspects in terms of the effects of CYP2C9 gene polymorphism on the pharmacokinetics of warfarin.…”

Section: Cyp2c9mentioning

confidence: 99%

Genetic Polymorphisms and <i>in Vitro</i> Functional Characterization of CYP2C8, CYP2C9, and CYP2C19 Allelic Variants

Hiratsuka

2016

Biological & Pharmaceutical Bulletin

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Genetic variations in CYP 2C (CYP2C) subfamily, CYP2C8, CYP2C9, and CYP2C19 contribute to interindividual variability in the metabolism of clinically used drugs. Changes in the drug metabolizing activity of CYP2C members may cause unexpected and serious adverse drug reactions and inadequate therapeutic effects. Therefore, CYP2C gene polymorphism is used as a genome biomarker for predicting responsiveness to administered drugs. The most direct method for understanding the extent of the effects of CYP2C gene polymorphism on drug pharmacokinetics is by evaluating the blood and urine concentrations of the drug in subjects. However, in vivo tests are highly invasive, and considering the risk of adverse drug reactions, the burden on the patient may be significant. In addition, examining the functions of rare variant enzymes with an allele frequency of ≤1% requires at least several hundred subjects. Furthermore, it is extremely difficult to evaluate the functions of all variant enzymes in an in vivo test. On the other hand, in vitro enzyme activity can be evaluated using a heterologous expression system to avoid the aforementioned problems. In vitro tests are extremely important as they complement in vivo information. This review focuses on recent findings of in vitro studies on 3 highly polymorphic CYP2C members: CYP2C8, CYP2C9, and CYP2C19.

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Effect of CYP2C9 and VKORC1 genotypes on early-phase and steady-state warfarin dosing in Korean patients with mechanical heart valve replacement

Abstract: The heterozygous CYP2C9 and VKORC1 genotypes influence warfarin dosing in an early phase as well as steady state of warfarin therapy in Korean patients with mechanical heart valve replacement.

Cited by 48 publications

References 34 publications

Warfarin Dose Requirements in a Patient with the CYP2C914* Allele

Warfarin Dose Requirements in a Patient with the CYP2C914* Allele

Discovery of a Novel Allelic Variant of CYP2C8, *CYP2C8**11, in Asian Populations and Its Clinical Effect on the Rosiglitazone Disposition In Vivo

Genetic Polymorphisms and <i>in Vitro</i> Functional Characterization of CYP2C8, CYP2C9, and CYP2C19 Allelic Variants

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Effect of CYP2C9 and VKORC1 genotypes on early-phase and steady-state warfarin dosing in Korean patients with mechanical heart valve replacement

Abstract: The heterozygous CYP2C9 and VKORC1 genotypes influence warfarin dosing in an early phase as well as steady state of warfarin therapy in Korean patients with mechanical heart valve replacement.

Cited by 48 publications

References 34 publications

Warfarin Dose Requirements in a Patient with the CYP2C9*14 Allele

Warfarin Dose Requirements in a Patient with the CYP2C9*14 Allele

Discovery of a Novel Allelic Variant of CYP2C8, CYP2C8*11, in Asian Populations and Its Clinical Effect on the Rosiglitazone Disposition In Vivo

Genetic Polymorphisms and <i>in Vitro</i> Functional Characterization of CYP2C8, CYP2C9, and CYP2C19 Allelic Variants

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Warfarin Dose Requirements in a Patient with the CYP2C914* Allele

Warfarin Dose Requirements in a Patient with the CYP2C914* Allele

Discovery of a Novel Allelic Variant of CYP2C8, *CYP2C8**11, in Asian Populations and Its Clinical Effect on the Rosiglitazone Disposition In Vivo