In vitro inhibitory effects of Kampo medicines on metabolic reactions catalyzed by human liver microsomes

BACKGROUND: Although it is well known that drug-drug interactions may lead to toxicity and therapeutic failure, little is known about the incidence and consequences of herb-drug interactions in patients receiving Kampo medicines. METHODS: We evaluated the frequency of the combined use of Kampo medicines and Western drugs at Osaka University Hospital, and investigated the effects of these formulae on the metabolic activity of different cytochrome P450 (CYP) isoforms using pooled microsomes obtained from human liver. RESULTS: Twenty-two Kampo formulae were used together with 40 Western drugs catalyzed by the CYP isoforms CYP3A4, CYP2C9, CYP2D6 and CYP1A2. Among the Kampo medicines, HOCHUEKKI-TO, SHOSAIKO-TO, NINJINYOUEI-TO, SAIREI-TO and KAKKON-TO were most frequently used during the study period (1996-2000). These were co-administered with 11 categories of drugs, which are substrates for CYP3A4. HOCHUEKKI-TO and SAIREI-TO were competitive inhibitors of CYP3A4 with Ki values of 0.65 and 0.1 mg/mL, respectively. HOCHUEKKI-TO, SHOSAIKO-TO and SAIREI-TO inhibited the metabolic activities of CYP2C9, but had no effect on CYP2D6. HOCHUEKKI-TO and SAIREI-TO exhibited non-competitive inhibition of the metabolic activity of CYP2C9 with a similar Ki value (0.7-0.8 mg/mL). SAIRE-TO (0.25 mg/mL) was a potent inhibitor of CYP1A2 (inhibition > 68%). CONCLUSIONS: Frequently used Kampo medicines may interact with Western drugs, which are substrates for CYP3A4, CYP2C9 and CYP1A2. Their co-administration should be undertaken with care.