title: Population estimation of the effects of cytochrome P450 2C9 and 2C19 polymorphisms on phenobarbital clearance in Japanese.
abstract: A nonlinear mixed-effect modeling (NONMEM) program was used to evaluate the effects of cytochrome P450 (CYP) 2C9 and CYP2C19 polymorphisms on the phenobarbital (PB) population clearance for Japanese epileptics. The pharmacokinetics of the 260 PB concentrations at a steady-state obtained from 79 patients was described with a one-compartment open pharmacokinetic model with first-order elimination. The covariates screened included the total body weight (BW), age, gender, PB daily dose, CYP2C9 and CYP2C19 genotypes, the coadministered antiepileptic drugs (AEDs), and complications. The final model of PB apparent clearance was as follows: CL = 0.23 x (BW/40)0.21 x 0.52CYP2C9*1/*3 x 0.68VPA x 0.85PHT x 0.85SMID x (1 + etaCL) where CL = the clearance of PB; CYP2C9*1/*3 = 1, otherwise 0; VPA = 1 if valproic acid is coadministered, otherwise 0; PHT = 1 if phenytoin is coadministered, otherwise 0; SMID = 1 if complications of severe or profound mental retardation with a significant behavior impairment are presented, otherwise 0; and etaCL = the independent random error distributed normally with the mean zero and variance equal to omegaP2. The total clearance of PB decreased by 48% in patients with CYP2C9*1/*3 genotype in comparison with those with CYP2C9*1/*1 genotype (P < 0.001). An effect of CYP2C19 polymorphisms was not detected. To our knowledge, this is the first report to demonstrate that the CYP2C9 genotype affects the PB metabolism in routine care, but the results should be further verified in other ethnic populations.
authors.affiliation: Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Goto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Seo
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Murata
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Nakada
authors.forename: Nao
authors.initials: N
authors.lastname: Ueda
authors.forename: Takateru
authors.initials: T
authors.lastname: Ishitsu
authors.forename: Kazuko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000328:Adult; D000465:Algorithms; D000927:Anticonvulsants / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D044466:Asian People / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D016903:Drug Monitoring / Q000379:methods; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005828:Genetics, Population; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007118:Immunoassay; D007555:Isoxazoles / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D007564:Japan; D008297:Male; D008657:Metabolic Clearance Rate; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D010634:Phenobarbital / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010672:Phenytoin / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D014635:Valproic Acid / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D000078305:Zonisamide
chemical_list: D000927:Anticonvulsants; D007555:Isoxazoles; D000078305:Zonisamide; D014635:Valproic Acid; D010672:Phenytoin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D010634:Phenobarbital