Genetic polymorphism of the CYP2C subfamily and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy*

Odani, Atsuko; Hashimoto, Yoshiaki; Otsuki, Yuko; Uwai, Yuichi; Hattori, Haruo; Furusho, Kenshi; Inui, Kenji

doi:10.1016/s0009-9236(97)90031-x

Cited by 145 publications

(87 citation statements)

References 13 publications

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“…For several CYP2C9 substrates, metabolism by the CYP2C9.3 enzyme variant is markedly reduced compared to the enzyme encoded by CYP2C9 * 1 [6,8,9] . This has clinical implications for CYP2C9 drugs with narrow therapeutic windows, such as warfarin and phenytoin, where drug accumulation due to slow metabolism will increase the risk of severe adverse reactions [10][11][12]. The primary objective of the present study was to assess the impact of CYP2C9 polymorphism on celecoxib oxidation in vitro , and to characterize further the enzymatic steps involved in the formation of carboxycelecoxib.…”

Section: Introductionmentioning

confidence: 99%

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase

Sandberg

Yaşar

Strömberg

et al. 2002

Brit J Clinical Pharma

102

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Aims Celecoxib is a novel selective cyclooxygenase-2 inhibitor, which is subject to extensive hepatic metabolism. The aims of the present in vitro investigation were 1) to compare the rate of celecoxib hydroxylation by different genetic variants of cytochrome P450 2C9 (CYP2C9), and 2) to identify the enzyme(s) involved in the formation of the major metabolite carboxycelecoxib. Methods Hydroxycelecoxib formation was studied in human liver microsomes from 35 genotyped livers, as well as in yeast microsomes with recombinant expression of different P450 variants. Carboxycelecoxib formation was studied in liver microsomes incubated in the absence or presence of liver cytosol. The metabolites were identified and quantified by h.p.l.c. In addition, hydroxycelecoxib oxidation by different variants of recombinant human alcohol dehydrogenase (ADH1-3) was analysed by spectrophotometric monitoring of NADH generation from NAD + . Results The intrinsic clearance of celecoxib hydroxylation was significantly lower for yeast-expressed CYP2C9.3 (0.14 ml min − 1 nmol − 1 enzyme) compared with CYP2C9.1 (0.44 ml min − 1 nmol − 1 enzyme). In human liver microsomes, a significant 2-fold decrease in the rate of hydroxycelecoxib formation was evident in CYP2C9 * 1/ * 3 samples compared with CYP2C9 * 1/ * 1 samples. There was also a marked reduction (up to 5.3 times) of hydroxycelecoxib formation in a liver sample genotyped as CYP2C9 * 3/ * 3 . However, the CYP2C9 * 2 samples did not differ significantly from CYP2C9 * 1 in any of the systems studied. Inhibition experiments with sulphaphenazole (SPZ) or triacetyloleandomycin indicated that celecoxib hydroxylation in human liver microsomes was mainly dependent on CYP2C9 and not CYP3A4. The further oxidation of hydroxycelecoxib to carboxycelecoxib was completely dependent on liver cytosol and NAD + . Additional experiments showed that ADH1 and ADH2 catalysed this reaction in vitro with apparent K m values of 42 µ M and 10 µ M , respectively, whereas ADH3 showed no activity. Conclusions The results confirm that CYP2C9 is the major enzyme for celecoxib hydroxylation in vitro and further indicate that the CYP2C9 * 3 allelic variant is associated with markedly slower metabolism. Furthermore, it was shown for the first time that carboxycelecoxib formation is dependent on cytosolic alcohol dehydrogenase, presumably ADH1 and/or ADH2.

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Section: Introductionmentioning

confidence: 99%

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase

Sandberg

Yaşar

Strömberg

et al. 2002

Brit J Clinical Pharma

102

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“…Genetic variation in the CYP2C9 gene can affect metabolism, leading to altered phenotypes. Individuals with poor metaboliser alleles of CYP2C9 gene were shown to have a reduced metabolism of phenobarbital, phenytoin and valproate compared with those with wild-type (normal) alleles [2][3][4][5][6][7][8][9] . Several studies indicate that the most common allelic variants are Arg 144 Cys (CYP2C9*2) and Ile 358 Leu (CYP2C9*3) which encode enzymes with decreased substrate turnover 10,11 .…”

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confidence: 99%

CYP2C9 polymorphism in patients with epilepsy: genotypic frequency analyzes andphenytoin adverse reactions correlation

Twardowschy

Werneck

Scola

et al. 2011

Arq. Neuro-Psiquiatr.

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Objective: CYP2C9 is a major enzyme in human drug metabolism and the polymorphism observed in the corresponding gene may affect therapeutic outcome during treatment. The distribution of variant CYP2C9 alleles and prevalence of phenytoin adverse reactions were hereby investigated in a population of patients diagnosed with epilepsy. Method: Allele-specific PCR analysis was carried out in order to determine frequencies of the two most common variant alleles, CYP2C9*2 and CYP2C9*3 in genomic DNA isolated from 100 epileptic patients. We also analyzed the frequency of phenytoin adverse reactions among those different genotypes groups. The data was presented as mean±standard deviation. Results: The mean age at enrollment was 39.6±10.3 years (range, 17-72 years) and duration of epilepsy was 26.5±11.9 years (range 3-48 years). The mean age at epilepsy onset was 13.1±12.4 years (range, 1 month-62 years). Frequencies of CYP2C9*1 (84%), CYP2C9*2 (9%) and CYP2C9*3 (7%) were similar to other published reports. Phenytoin adverse reactions were usually mild and occurred in 15% patients, without correlation with the CYP2C9 polymorphism (p=0.34). Conclusion: Our findings indicate an overall similar distribution of the CYP2C9 alleles in a population of patients diagnosed with epilepsy in the South of Brazil, compared to other samples. This sample of phenytoin users showed no drug related adverse reactions and CYP2C9 allele type correlation. The role of CYP2C9 polymorphism influence on phenytoin adverse reaction remains to be determined since some literature evidence and our data found negative results. Key words: CYP2C9, polymorphism, Brazilian population, phenytoin, adverse reactions.Polimorfismo do CYP2C9 em pacientes com epilepsia: estudo da frequência genotípica e correlação com os efeitos colaterais da fenitoína RESUMO Objetivo: A CYP2C9 é uma das principais enzimas do metabolismo de drogas humano e o polimorfismo observado no respectivo gene pode afetar o resultado terapêutico durante o tratamento. Neste trabalho investigamos em uma população de pacientes portadores de epilepsia a distribuição dos alelos variantes do CYP2C9 e a frequência de efeitos adversos da fenitoína tentando estabelecer uma correlação. Método: Realizamos uma análise através de uma PCR alelo específica para determinar a frequência dos alelos variantes mais comuns, CYP2C9*2 e CYP2C9*3, isolados da amostra de 100 pacientes com epilepsia. Também levantamos a frequência de reações adversas da fenitoína nestes diferentes grupos genotípicos. Os dados são apresentados na forma de média e desviopadrão. Resultados: A idade média na inclusão foi 39,6±10,3 anos (variando de 17-72 anos) e a duração da epilepsia era 26,5±11,9 anos (variando de 3-48 anos). A idade média dos pacientes no início da epilepsia era 13,1±12,4 anos (variando de 1 mês-62 anos). As frequências do CYP2C9*1 (84%), CYP2C9*2 (9%) e CYP2C9*3 (7%) foram similares Correspondence Carlos Silvado Hospital de Clínicas / UFPR Rua General Carneiro 181 / 3° andar 80060-900 Curitiba PR -Brasil

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“…On the other hand, previous in vivo studies showed that individuals who were genotyped as CYP2C9*3 reduced the clearance of S-warfarin, tolbutamide and phenytoin. [6][7][8] Also, expression systems of CYP enzymes have been used to investigate the catalytic activities of the enzymes in vitro, and the Leu 359 variant significantly affected the kinetic parameters in vitro, such as S-warfarin, 9 tolbutamide 7 and torsemide. 10 However, there has been no study on the CYP2C9 catalytic property of candesartan.…”

Section: Introductionmentioning

confidence: 99%

CYP2C9*3 influences the metabolism and the drug-interaction of candesartan in vitro

et al. 2001

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Candesartan cilexetil is an angiotensin II receptor antagonist, and candesartan, its active metabolite, is metabolized by CYP2C9. However, the effect of CYP2C9*3 on candesartan metabolism is not established. We characterized the kinetics of candesartan by CYP2C9*1/*1 and CYP2C9*1/*3 in human liver microsomes. The difference between the two was not significant. Subsequently, CYP2C9*1 and CYP2C9*3 (Leu 359 ) were expressed in yeast, and the kinetics of candesartan were determined. The wild-type showed the lower K m (345 vs 439 M; 3/4) and higher V max /K m (1/3) than the Leu 359 variant. Also, we investigated potential interaction between candesartan and warfarin with both the wild-type and the Leu 359 variant. Candesartan had no effect on S-warfarin 7-hydroxylation. In contrast, S-warfarin inhibited candesartan metabolism by the wild-type (K i = 17 M) greater than by the Leu 359 variant (K i = 36 M). These findings suggest that CYP2C9*3 may change not only the metabolic activity but also the inhibitory susceptibility compared with

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Genetic polymorphism of the CYP2C subfamily and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy*

Abstract: The findings indicated that the genetic polymorphisms of CYP2C isozymes play an important role in the pharmacokinetic variability of phenytoin and that the mutation in CYP2C9 proteins (Ile359-->Leu) is a determinant of impaired metabolism of the drug among Japanese persons.

Cited by 145 publications

References 13 publications

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase

CYP2C9 polymorphism in patients with epilepsy: genotypic frequency analyzes andphenytoin adverse reactions correlation

CYP2C9*3 influences the metabolism and the drug-interaction of candesartan in vitro

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