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Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin
Author(s) -
Brockmöller Jürgen,
Bauer Steffen,
Sachse Christoph,
Güzelbey Pinar,
Öngen Zuhal,
Nacak Muradiye,
Roots Ivar
Publication year - 1999
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1999.00012.x
Subject(s) - cyp2c9 , phenytoin , turkish population , genotype , population , cytochrome p450 , pharmacology , polymorphism (computer science) , medicine , chemistry , endocrinology , biology , genetics , metabolism , epilepsy , gene , environmental health , neuroscience
Aims The genetically polymorphic cytochrome P450 enzyme CYP2C9 metabolizes many important drugs. We studied the frequency of the amino acid variants cysteine 144 (CYP2C9*2 ) and leucine 359 (CYP2C9*3 ) in a Turkish population and the correlation between genotype and phenotype using phenytoin as probe drug.Methods CYP2C9 alleles *2 and *3 were measured in 499 unrelated Turkish subjects by PCR and restriction fragment length pattern analysis. Phenotyping was performed in a subgroup of 101 volunteers with a single oral dose of 300 mg phenytoin and concentration analysis in serum drawn 12 h after dosage.Results CYP2C9 allele frequencies in 499 unrelated Turkish subjects were 0.794 for CYP2C9*1, 0.106 for CYP2C9*2 and 0.100 for CYP2C9*3. Mean phenytoin serum concentrations at 12 h after dosage were 4.16 mg l −1 (95% CI 3.86–4.46) in carriers of the genotype CYP2C9*1/1, 5.52 mg l −1 (4.66–6.39) in CYP2C9*1/2, and 5.65 mg l −1 (4.86–6.43) in CYP2C9*1/3. These differences were significant and accounted for 31% of total variability in phenytoin trough levels. Mean 12 h concentration ratios of 5‐(para‐hydroxyphenyl)‐5‐phenylhydantoin/phenytoin (p‐HPPH/P) were 0.43 (0.39–0.47) for CYP2C9*1/1 compared with 0.26 (0.21–0.31) for CYP2C9*1/2, 0.14 (0.13–0.14) for CYP2C9*2/2, 0.21 (0.18–0.24) for CYP2C9*1/3, and 0.02 for CYP2C9*3/3; all mutant genotypes were significantly different compared with CYP2C9*1/1 .Conclusions Frequency of the two CYP2C9 variants in Turkish subjects was in a similar range as in other Caucasian populations. A significant proportion of the interindividual variability in phenytoin trough levels is explained by the genotypes. The 12 h serum concentrations after a single phenytoin dose may be used for routine phenotyping of CYP2C9 mediated metabolic clearance and the p‐HPPH/P ratios may be even more sensitive indicators of CYP2C9 activity.