alexa A pharmacodynamic-pharmacokinetic (PD-PK) study on the effects of Danshen (Salvia miltiorrhiza) on midazolam, a model CYP3A probe substrate, in the rat.
Pharmaceutical Sciences

Pharmaceutical Sciences

Pharmaceutica Analytica Acta

Author(s): Wang X, Lee WY, Zhou X, Or PM, Yeung JH

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Abstract This study investigated the effect of Danshen on the pharmacodynamic-pharmacokinetic (PD-PK) effects of midazolam, a model CYP3A probe substrate. The effects of acute and 3-day Danshen treatment on the pharmacokinetics of a low dose midazolam (10 mg/kg, i.p.) were determined in vivo in the rat. Danshen (200 mg/kg, i.p.) treatment decreased midazolam clearance by 16\%, with increases in the AUC by 22\% and the half-life by 14\%. 3-Day Danshen treatment (200 mg/kg/day, i.p.) for 3 days decreased the clearance, with increases in the T(1/2) and AUC. The effects of acute and 3-day Danshen on midazolam-induced hypnosis, serum 1'-hydroxy-midazolam to midazolam ratio and hepatic CYP3A protein expression were determined in the rat. Danshen treatments (100-200 mg/kg, i.p. and 200-500 mg/kg, p.o.) increased the sleeping time (p<0.001) produced by a hypnotic dose of midazolam (50 mg/kg, i.p.) without affecting the sleep latency. Serum 1'-hydroxy-midazolam to midazolam ratio after the hypnotic dose of midazolam was decreased after intraperitoneal Danshen treatment (200 mg/kg) but not after oral treatment at up to 500 mg/kg. All the treatment groups with Danshen, after intraperitoneal and oral administration, decreased hepatic CYP3A protein expression (p<0.05) by about 25\%. The results confirmed that Danshen had no enzyme inducing effects on rat CYP3A. Copyright 2010 Elsevier GmbH. All rights reserved. This article was published in Phytomedicine and referenced in Pharmaceutica Analytica Acta

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