Effects of the aqueous extract from Salvia miltiorrhiza Bge on the pharmacokinetics of diazepam and on liver microsomal cytochrome P450 enzyme activity in rats

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Abstract
The aim of this study was to determine the effects of the aqueous extract of Salvia miltiorrhiza Bge (danshen in Chinese) on the pharmacokinetics of diazepam and on liver microsomal cytochrome P450 enzyme activity in rats. Rats (n = 5) were pretreated with danshen extract (100 mg kg−1 per day, p.o.) for 15 consecutive days. Control rats (n = 5) received saline at the same time. Each rat was then administered a single oral dose of 15 mg kg−1 diazepam. The pharmacokinetic parameters of diazepam were significantly different between the two groups. In the danshen pretreated group, the maximum concentration of diazepam and the area under the plasma concentration–time curve were reduced to about 72.7% and 44.4%, respectively, while the total body clearance was markedly increased by 2-fold. To help explain the results, liver microsomal suspensions were obtained from rats that were randomly divided into the control group (n = 10), and the low- (20 mg kg−1 for 15 days, p.o., n = 10) and high-dose groups (100 mg kg−1 for 15 days, p.o., n = 10) pretreated with danshen extract. Compared with the control rats, the microsomal protein content, cytochrome P450 enzyme level and erythromycin N-demethylase activity of pretreated rats were significantly increased. These results indicate that danshen extract can stimulate the activity of cytochrome P450 isoforms, and changes in the pharmacokinetics of diazepam resulting from danshen extract are related to an increase in metabolic activity of cytochrome P450.

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