Effects of Schisandra sphenanthera extract on the pharmacokinetics of midazolam in healthy volunteers.
OBJECTIVE
To assess the effect of Schisandra sphenanthera extract (SchE) on the pharmacokinetics of midazolam, a probe drug of CYP3A, and its metabolite 1'-hydroxy midazolam in healthy volunteers.


METHODS
Twelve healthy male volunteers were orally treated with SchE, three capsules twice daily for 7 days. Pharmacokinetic investigations of oral midazolam administration at 15 mg were performed both before and at the end of the SchE treatment period. The plasma midazolam and 1'-hydroxy midazolam concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry. Estimated pharmacokinetic parameters before and with SchE were calculated with noncompartmental techniques.


RESULTS
Following administration of SchE, the average increases (%) of individual increases in AUC, AUMC and C(max) of midazolam were 119.4% [95% confidence interval (CI) 83.9, 155.0], 183.4% (95% CI 120.5, 246.2) and 85.6% (95% CI 14.4, 156.9), respectively (P < 0.01 or 0.05). On average, there was a 133.3% (95% CI 8.9, 257.7) increase in midazolam t(max) (P < 0.01). The average decrease (%) in CL/F was 52.1% (95% CI 44.9, 59.4) (P < 0.01). No significant changes were seen in midazolam half-life. After co-administration of SchE, the average increase (%) in t(max) of 1'-hydroxy midazolam was 150.0% (95% CI 22.2, 277.8) (P < 0.05). No significant differences were observed in the other pharmacokinetic parameters of 1'-hydroxy midazolam.


CONCLUSIONS
SchE can markedly increase the oral bioavailability of midazolam in healthy volunteers. SchE is an inhibitor of CYP3A and has a high susceptibility to alter the disposition of drugs metabolized by CYP3A.
Xin
Hua-Wen
HW
Department of Clinical Pharmacology, Wuhan General Hospital of Guangzhou Command, China. huawenxin@163.com
Wu
Xiao-Chun
XC
Li
Qing
Q
Yu
Ai-Rong
AR
Xiong
Lei
L
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D010936:Plant Extracts / Q000494:pharmacology*; D032141:Schisandra / Q000187:drug effects*; D055815:Young Adult
D010936:Plant Extracts; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam