Effects of Schisandra sphenanthera extract on the pharmacokinetics of midazolam in healthy volunteers
Effects of Schisandra sphenanthera extract on the pharmacokinetics of midazolam in healthy volunteers
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DOI：
10.1111/j.1365-2125.2009.03383.x
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发表时间：
2009-05-01
影响因子：
3.4
通讯作者：
Xiong, Lei
中科院分区：
文献类型：
--
作者：
Xin, Hua-Wen;Wu, Xiao-Chun;Xiong, Lei
在肾和肝移植受者的治疗中，常同时给予华中五味子提取物（SchE）和他克莫司China.center我们以前的研究表明SchE可以增加他克莫司的口服生物利用度。本研究的结果表明SchE可以显著增加健康受者咪达唑仑的血药浓度和口服生物利用度volunteers.center。这一发现表明SchE可能是CYP 3A的抑制剂，并且可能改变经CYP 3A代谢的药物的处置。为了评估南五味子提取物（Schisandra sphenanthera extract，SchE）对健康志愿者体内CYP 3A探针药物咪达唑仑及其代谢物1 '-羟基咪达唑仑药代动力学的影响。12名健康男性志愿者口服SchE，每天两次，每次三粒，持续7天。在SchE治疗期之前和结束时进行了15 mg咪达唑仑口服给药的药代动力学研究。采用高效液相色谱-串联质谱法测定血浆咪达唑仑和1 '-羟基咪达唑仑浓度。SchE给药后，咪达唑仑AUC、AUMC和C（max）的平均增幅（%）分别为119.4% [95%可信区间（CI）83.9，155.0]，183.4%[95%可信区间（CI）83.9，155.0]。（95% CI 120.5，246.2）和85.6%（95% CI 14.4，156.9）（P < 0.01或0.05）。咪达唑仑组t（max）平均增加133.3%（95%CI 8.9，257.7）（P < 0.01）。CL/F平均下降52.1%（95% CI 44.9，59.4）（P < 0.01）。未观察到咪达唑仑半衰期的显著变化。与SchE合用后，1 '-羟基咪达唑仑的t（max）平均增加150.0%（95%CI 22.2，277.8）（P < 0.05）。SchE能显著提高健康志愿者口服1 '-羟基咪达唑仑的生物利用度。SchE是CYP 3A的抑制剂，对改变CYP 3A代谢药物的处置具有高度敏感性。
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTcenter dot Schisandra sphenanthera extract (SchE) and tacrolimus are often co-administered in treating renal and liver transplant recipients in China.center dot Our previous study has demonstrated that SchE can increase the oral bioavailability of tacrolimus.WHAT THIS STUDY ADDScenter dot The results of this study show that SchE can markedly increase the blood concentration and oral bioavailability of midazolam in healthy volunteers.center dot 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.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.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.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.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.