Interaction of drugs and Chinese herbs: Pharmacokinetic changes of tolbutamide and diazepam caused by extract of Angelica dahurica

The inhibitory effects of Angelica dahurica root extract on rat liver micro somal cytochrome P450 and drug-drug interactions were studied. The 2 alpha- and 16 alpha-hydroxylase activity of testosterone were most st rongly inhibited, with 17.2% and 28.5% of their activity remaining, respect ively, after oral administration of A. dahurica extract at a 1 g kg(-1) dos e. 6 beta-Hydroxylase activity was also inhibited, with 70% of its activity remaining, under the same conditions. In addition, treatment with the extr act inhibited the metabolism of tolbutamide, nifedipine and bufuralol. Thes e results showed that the extract inhibited the various isoforms of cytochr ome P450 such as CYP2C, CYP3A and CYP2D1. The A. dahurica extract delayed elimination of tolbutamide after intravenou s administration at a 10 mg kg(-1) dose to rats. Thus, the extract altered the liver intrinsic clearance. It had little effect, however, on the pharma cokinetic parameters of diazepam after intravenous administration at 10 mg kg(-1). Since diazepam showed high clearance, it underwent hepatic blood fl ow rate-limited metabolism. Therefore, the change of intrinsic clearance ha d little effect on hepatic clearance. However, the C-max value after oral a dministration of diazepam with extract treatment was four times that with n on-treatment. It was suggested that the first-pass effect was changed marke dly by the extract. High-dose(1 g kg(-1)), but not low dose (0.3 g kg(-1)), administration of A. dahurica extract increased significantly the duration of rotarod disruption following intravenous administration of diazepam at 5 mg kg(-1) It was concluded that administration of A. dahurica extract has the potenti al to interfere with the metabolism, by liver cytochrome P450, of other dru gs.