Evaluation of Herb-drug Interaction in Healthy Subjects by Comparing the Cytochrome P450 Activities before and after Multiple Administrations of Herbal Medicines

건강한 자원자에서 한약 반복투여 전후의 Cytochrome P450 대사능 변화 평가를 통한 한약과 양약의 상호작용 연구

Objectives : The aims of this study were to investigate the effect of three herbal medicines {Ephedra sinica(ma-huang), Scutellaria baicalensis(baical skullcap), Aconitum carmichaeli (aconite)} on cytochrome P450(CYP) activities. A cocktail approach was used to determine whether multiple administration of herbal medicines affects CYP1A2, CYP 2C19, CYP2E1 and CYP3A4 activities. Methods : The study was done as an open-label, randomized, positive-controlled, parallel group study. Twenty four healthy male subjects were randomly allocated to receive ma-huang, baical skullcap, aconite or St. John's wort for 12 days, respectively. They were prepared in extract formulations. Probe drugs for CYP1A2, CYP2C19, CYP2E1, and CYP3A4 were caffeine, omeprazole, chlorzoxazone and midazolam. All of them except chlorzoxazone were administrated by the validated forms of cocktail approach. The activities of CYP enzymes were analyzed by measuring probe drug and metabolite concentration in the blood; paraxanthine/caffeine plasma ratio(6 hour after administrated) for CYP1A2, 5-OH-omeprazole/omeprazole plasma ratio(2 hour) for CYP2C19, 6-OH-chlorzoxazone/chlorzoxazone plasma ratio(2 hour) for CYP2E1, and l-OH-midazolam/midazolam plasma ration(1, 2, 6 hour, respectively) for CYP3A4. The analytic procedure was done by HPLC assays. Results : Comparisons of pre- and post-medication phenotyping results showed that aconite significantly inhibited CYP2E1 activity by $48{\pm}4%(P=0.0312)$. Baical skullcap showed the trends of inhibiting CYP1A2 activity(P=0.2188). CYP2Cl9 enzyme activity was induced by $140{\pm}130%$ in St. John's wort medication group(P=0.0769). Also in St. John's wort group, CYP3A4 enzyme activity was induced by $450{\pm}750%$ after 2 hour-administration of midazolam(P=0.00625), however, the last three results were not significant in a statistical analysis. Conclusions : The CYP2E1 inhibition of Amnitum carmidueli could have hepatoprotective functions from xenobiotics.