Effects of Schisandra sphenanthera extract on the pharmacokinetics of midazolam in healthy volunteers

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Schisandra sphenanthera extract (SchE) and tacrolimus are often co-administered in treating renal and liver transplant recipients in China. • Our previous study has demonstrated that SchE can increase the oral bioavailability of tacrolimus. WHAT THIS STUDY ADDS • The results of this study show that SchE can markedly increase the blood concentration and oral bioavailability of midazolam in healthy volunteers. • This finding suggests that SchE may be an inhibitor of CYP3A and is likely to alter the disposition of drugs that are metabolized by CYP3A. AIMS 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.