A herbal-drug interaction study of keishi-bukuryo-gan, a traditional herbal preparation used for menopausal symptoms, in healthy female volunteers.

OBJECTIVES: Many patients use herbal medicines to relieve menopausal symptoms. Keishi-bukuryo-gan contains five herbal components, and has been used for treating hypermenorrhoea, dysmenorrhoea and menopausal symptoms in Asian countries. In this study, we investigated the potential herb-drug interactions of keishi-bukuryo-gan in healthy female subjects. METHODS: Thirty-one healthy females (20-27 years) were studied to evaluate their baseline activity of cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, xanthine oxidase (XO) and N-acetyltransferase 2 (NAT2) based on the urinary metabolic indices of an 8-h urine sample collected after a 150-mg dose of caffeine and a 30-mg dose of dextromethorphan, and also the urinary excretion ratio of 6ß-hydroxycortisol to cortisol. Thereafter, the subjects received 3.75g of keishi-bukuryo-gan twice daily for seven days, and underwent the same tests on post-dose day 7. KEY FINDINGS: The geometric mean phenotypic index for CYP1A2 significantly decreased by 16% on day 7 compared with the baseline (P=0.026). Keishi-bukuryo-gan did not alter the indices for CYP2D6, CYP3A, XO and NAT2. CONCLUSIONS: Keishi-bukuryo-gan may inhibit the activity of CYP1A2, which is predominantly involved in oestrogen metabolism. However, TJ-25 is unlikely to participate in herb-drug interactions involving medications predominantly metabolized by CYP2D6, CYP3A, XO and NAT2. K

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. CONCLUSION: CYP2C19 genotype had an impact on the efficacy of clobazam, thus indicating that N-clobazam plays an important role in long-term clobazam therapy.