A major influence of CYP2C19 genotype on the steady-state concentration of N-desmethylclobazam.
N-desmethylclobazam (N-CLB), the major metabolite of clobazam (CLB), exerts a large influence on therapeutic and adverse effects of CLB. A substantial inter-individual variability has been observed in the ratios of N-CLB concentration/CLB dose and of the N-CLB/CLB concentration. We document here a genotype-phenotype correlation between CYP2C19 polymorphisms and those ratios. Patients with two mutated CYP2C19 alleles show significantly higher ratios than those with the wild type genotype: patients with one mutated allele exhibited intermediate trait. That is, the degree of elevation in the ratios was dependent on the number of mutated alleles of CYP2C19 (gene-dose effect). The N-CLB concentration/CLB dose ratio of patients with two mutated alleles was more than six fold higher than that of wild type patients. Thus, the serum N-CLB/CLB concentration ratio may be a valuable parameter to screen for patients at risk for side effects. Such precautions may be clinically relevant in populations where the mutant allele frequency is high, such as in Asian populations ( approximately 35%). Patients co-medicated with CYP3A4 inducer showed lower CLB concentration/CLB dose ratios and higher N-CLB/CLB concentration ratios. The overall effect of CYP3A4 inducer on N-CLB metabolism, however, was small and, thus, we conclude that the CYP2C19 genotype is the major determinant of the N-CLB concentration. For this reason it is crucial for the better management of epilepsy and other chronic illnesses in general to establish the correlation of genotype of CYP enzymes and pharmacokinetics/dynamics of drugs.
Kosaki
Kenjiro
K
Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Tamura
Kazuyo
K
Sato
Reiko
R
Samejima
Hazuki
H
Tanigawara
Yusuke
Y
Takahashi
Takao
T
D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001569:Benzodiazepines / Q000097:blood* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D000078306:Clobazam; D065731:Cytochrome P-450 CYP2C19; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics*; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007223:Infant; D007564:Japan / Q000208:ethnology; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic
D000927:Anticonvulsants; D001569:Benzodiazepines; D000078306:Clobazam; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; C024581:N-desmethylclobazam