Impact of CYP2C19 polymorphisms on the efficacy of clobazam therapy.
BACKGROUND
Clobazam-induced adverse reactions have been reported in cases with CYP2C19 defective allele(s). However, the relevance of the CYP2C19 genotypes to clobazam therapy remains to be clarified.


METHODS
The association between CYP2C19 genotypes and the antiepileptic and adverse effects of clobazam was retrospectively investigated in 110 Japanese subjects, in relation to clobazam and N-desmethylclobazam (N-clobazam) concentrations.


RESULTS
There were 41 (37.3%) homozygous extensive metabolizers (EMs), 44 (40.0%) heterozygous EMs, and 25 (22.7%) poor metabolizers (PMs). The response rate was significantly greater in PMs and heterozygous EMs than homozygous EMs with a gene-dose effect (65.2, 47.6 and 33.3%, respectively), and the adjusted odds ratio (95% CI) of PM versus homozygous EMs was 9.88 (2.47-39.56; p = 0.001). However, the genotypes did not affect the development of tolerance or adverse reactions, although the incidence of some adverse symptoms was insignificantly higher in PMs. The N-clobazam concentration (microg/ml) increased with the number of CYP2C19-defective alleles (0.92 +/- 0.61, 2.14 +/- 1.69 and 7.70 +/- 6.04, respectively; p < 0.001), while the clobazam concentration was 1.5-fold greater in those with at least one variant.


CONCLUSIONS
CYP2C19 genotype had an impact on the efficacy of clobazam, thus indicating that N-clobazam plays an important role in long-term clobazam therapy.
Seo
Takayuki
T
Kumamoto University, Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Science, Oe-honmachi 5-1, Kumamoto 862-0973, Japan.
Nagata
Rie
R
Ishitsu
Takateru
T
Murata
Tsukasa
T
Takaishi
Chisato
C
Hori
Masaharu
M
Nakagawa
Kazuko
K
D000293:Adolescent; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001569:Benzodiazepines / Q000627:therapeutic use*; D002648:Child; D000078306:Clobazam; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D012189:Retrospective Studies
D001569:Benzodiazepines; D000078306:Clobazam; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19