Summary:Purpose: The aim of this study was to clarify the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C9 and 2C19 on the metabolism of phenytoin (PHT). In addition, a population pharmacokinetic analysis was performed.Methods: The genotype of CYP2C9 (Arg'44/Cys, Ile359/Leu) and CYP2C19 (*l, *2 or *3) in 134 Japanese adult patients with epilepsy treated with PHT were determined, and their serum concentrations of 5-(4-hydroxyphenyl)-5-phenylhydantoin @-HPPH) enantiomers, being major metabolites of PHT, were measured. A population pharmacokinetic analysis (NONMEM analysis) was performed to evaluate whether genetic polymorphism of CYP2C9/19 affects the clinical use of PHT by using the 336 dose-serum concentration data.Results: The mean maximal elimination rate (Vmax) was 42% lower in the heterozygote for Leu359 allele in CYP2C9, and the mean Michaelis-Menten constants (K,) in the heterozygous extensive metabolizers and the poor metabolizers of CYP2C19 were 22 and 54%, respectively, higher than those without the mutations in CYP2C9/19 genes. (R)-and (5')-p-HPPHPHT ratios were lower in patients with mutations in CYP2C9 or CYP2C19 gene than those in patients without rnutations.Conclusions: Although the hydroxylation capacity of PHT was impaired with mutations of CYP2C9/19, the impairment was greater for CYP2C9. In view of the clinical use of PHT, two important conclusions were derived from this population study. First, the serum PHT concentration in patients with the Leu359 allele in CYP2C9 would increase dramatically even at lower daily doses. Second, the patients with CYP2C19 mutations should be treated carefully at higher daily doses of PHT.Key Words: Phenytoin-CYP2C9-CYP2C19-Genetic polymorphism-NONMEM.Phenytoin (PHT), a widely prescribed anticonvulsant (AED), is a prochiral compound that is eliminated in humans almost entirely by cytochrome P450 (CYP)-mediated oxidation (1.2). Although the major advantage of its clinical use is that a relation between serum concentration and therapeutic effect has been established, it is sometimes difficult to adjust the dose of PHT to attain a therapeutic drug concentration because of the variability in its pharmacokinetic properties [e.g., capacity limited metabolism (3,4)]. The principal metabolic pathway is formation of 5-(4-hydroxyphenyl)-5-phenylhydantoin @-HPPH) that exists as (R)-and (S)-enantiomers and accounts for -90% of total urinary metabolites (5). The results bf recent human liver microsomal kinetic (2,6-8),

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Key wordsThe P300 event-related potentials in response to self-relevant stimuli has been reported to be different from those to non-target stimuli under a passive attention condition. In the present study the P300 in response to the subject's own face was examined. Twelve right-handed volunteers served as subjects. In two separate conditions, deviant (subject's own face and red square; 30%), nontarget (two unfamiliar faces; 30% each), and target (famous face; 10%) stimuli were randomly presented on a computer screen. P300 amplitudes in response to the red square were larger than those to the unfamiliar faces, but were significantly lower than those to the subject's own face. The subject's own face in normal population may have an intense relevance to the subjects which has an additional effect over the simple orienting response. deviant stimulus, event-related potentials, face, orienting response, P300, self relevance.

Our data indicate that at least one susceptibility locus for schizophrenia is situated within or very close to the GRM3 region in the Japanese patients.

The human dopamine D4 receptor (DRD4) is of major interest in molecular studies of schizophrenia and personality traits. We examined the association of schizophrenia and polymorphisms in the upstream region of the DRD4 gene (Ϫ768GϾA in the negative modulator region; Ϫ521CϾT, Ϫ376CϾT, and Ϫ291CϾT in the cell typespecific promoter region; and Ϫ616CϾG between the two regions) in 208 schizophrenic patients and 210 normal controls. No significant difference in genotype and allele frequencies was observed between the two groups, indicating that these polymorphisms do not make a major contribution to the pathogenesis of schizophrenia. We also studied the association of polymorphisms in the upstream region and a 48-bp repeat polymorphism in exon III of the DRD4 gene with personality traits in 173 Japanese individuals who completed the temperament and character inventory (TCI). The Ϫ768GϾA polymorphism was significantly associated with reward dependence (P ϭ 0.044), while no significant association was observed between novelty seeking and polymorphisms in the upstream region or the exon III repeat polymorphism of the DRD4 gene.