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

Phytomedicine. 2010 Sep;17(11):876-83. doi: 10.1016/j.phymed.2010.05.007. Epub 2010 Jul 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Area Under Curve
  • Cytochrome P-450 CYP3A / metabolism*
  • Drugs, Chinese Herbal / administration & dosage
  • Drugs, Chinese Herbal / pharmacology*
  • Half-Life
  • Herb-Drug Interactions*
  • Hypnotics and Sedatives / pharmacokinetics
  • Hypnotics and Sedatives / pharmacology*
  • Liver / metabolism
  • Male
  • Metabolic Clearance Rate / drug effects
  • Midazolam / pharmacokinetics
  • Midazolam / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Salvia miltiorrhiza*
  • Sleep / drug effects*

Substances

  • Drugs, Chinese Herbal
  • Hypnotics and Sedatives
  • Cytochrome P-450 CYP3A
  • Midazolam