title: Effects of CYP2C19 and P450 oxidoreductase polymorphisms on the population pharmacokinetics of clobazam and N-desmethylclobazam in japanese patients with epilepsy.
abstract: BACKGROUND
  Clobazam (CLB) is a 1,5-benzodiazepine with antiepileptic properties. More than 70% of administered CLB is dealkylated to yield N-desmethylclobazam (N-CLB), a pharmacologically active metabolite, by cytochrome P450 (CYP) 3A4 and CYP2C19. The subsequent inactivation of N-CLB is primarily catalyzed by CYP2C19. Meanwhile, P450 oxidoreductase (POR) is the obligatory electron donor to all microsomal CYP enzymes. The aim of this study was to evaluate the impact of the CYP2C19 and POR genotypes on the pharmacokinetic parameters of CLB and N-CLB.
  
  
  METHODS
  This retrospective study included 85 Japanese patients with epilepsy who were treated with CLB. CYP2C19*2, *3, and P450 oxidoreductase (POR) *28 (rs1057868C>T) polymorphisms were evaluated. A total of 128 steady-state concentrations for both CLB and N-CLB were collected from the patients. A nonlinear mixed-effects model identified the pharmacokinetics of CLB and N-CLB; the covariates included CYP2C19 and POR genotypes, weight, gender, daily CLB dose, and coadministered antiepileptic drugs.
  
  
  RESULTS
  Among the 85 patients, the allele frequencies of CYP2C19*2, CYP2C19*3, and POR*28 were 27.6%, 12.9%, and 41.2%, respectively. A one-compartment model with first-order absorption and/or elimination showed that the clearance of CLB and N-CLB was significantly lower by 18.1% and 84.9%, respectively, in the CYP2C19 poor metabolizers compared with the homozygous extensive metabolizers. The CLB clearance was 44% higher in subjects homozygous for the POR*28 T allele than in those homozygous for the POR*28 C allele, although the genotypes did not affect the N-CLB clearance. The concomitant use of phenobarbital, phenytoin, and zonisamide significantly affected the CLB clearance, whereas that of carbamazepine, phenytoin, and valproic acid affected the N-CLB clearance. The weight also significantly influenced the CLB clearance and volume of distribution of both CLB and N-CLB.
  
  
  CONCLUSIONS
  Our results showed that the CYP2C19 and/or POR genotypes have an impact on the CLB and/or N-CLB clearance. These results suggest that determining the CYP2C19 and/or POR genotypes is helpful for obtaining appropriate serum CLB and N-CLB concentrations and preventing an overdose when starting CLB therapy.
authors.affiliation: *Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; †Department of Hospital Pharmacy, Yanagisawa Hospital, Ueda, Japan; ‡Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan; §Department of Pediatrics, Kumamoto Saishunso National Hospital, Kumamoto, Japan; and ¶Center for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Saruwatari
authors.forename: Naoki
authors.initials: N
authors.lastname: Ogusu
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Shimomasuda
authors.forename: Hiroo
authors.initials: H
authors.lastname: Nakashima
authors.forename: Takayuki
authors.initials: T
authors.lastname: Seo
authors.forename: Koji
authors.initials: K
authors.lastname: Tanikawa
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Miki
authors.initials: M
authors.lastname: Nishimura
authors.forename: Rie
authors.initials: R
authors.lastname: Nagata
authors.forename: Norio
authors.initials: N
authors.lastname: Yasui-Furukori
authors.forename: Sunao
authors.initials: S
authors.lastname: Kaneko
authors.forename: Takateru
authors.initials: T
authors.lastname: Ishitsu
authors.forename: Kazuko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D000078306:Clobazam; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D007564:Japan; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D012737:Sex Factors
chemical_list: D000927:Anticonvulsants; D001569:Benzodiazepines; D000078306:Clobazam; D065731:Cytochrome P-450 CYP2C19; D009251:NADPH-Ferrihemoprotein Reductase; C024581:N-desmethylclobazam