A pharmacodynamic-pharmacokinetic (PD-PK) study on the effects of Danshen (Salvia miltiorrhiza) on midazolam, a model CYP3A probe substrate, in the rat.
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.
Wang
Xin
X
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China.
Lee
Wayne Y W
WY
Zhou
Xuelin
X
Or
Penelope M Y
PM
Yeung
John H K
JH
D000818:Animals; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000494:pharmacology*; D006207:Half-Life; D041743:Herb-Drug Interactions; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008874:Midazolam / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D027561:Salvia miltiorrhiza; D012890:Sleep / Q000187:drug effects*
D004365:Drugs, Chinese Herbal; D006993:Hypnotics and Sedatives; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam