五味子甲素对大鼠咪达唑仑及其代谢物1′-羟基咪达唑仑药动学影响

中国临床药理学与治疗学 ›› 2012, Vol. 17 ›› Issue (3): 245-250.

五味子甲素对大鼠咪达唑仑及其代谢物1′-羟基咪达唑仑药动学影响

辛华雯, 李维亮, 吴笑春, 李罄, 余爱荣

广州军区武汉总医院临床药理科,武汉 430070,湖北

收稿日期:2011-10-27 修回日期:2012-01-27 出版日期:2012-03-26 发布日期:2012-04-20
作者简介:辛华雯,女,主任医师,硕士生导师,研究方向:临床药理学。Tel: 027-68878688, E-mail: huawenxin@163.com
基金资助:
湖北省卫生厅科研基金资助(JX3B38)

Effects of Schisandrin A on pharmacokinetics of midazolam and its metabolite in rats

XIN Hua-wen, LI Wei-liang, WU Xiao-chun, LI Qing, YU Ai-rong

Department of Clinical Pharmacology, Wuhan General Hospital of Guangzhou Command, Wuhan 430070, Hubei, China

Received:2011-10-27 Revised:2012-01-27 Online:2012-03-26 Published:2012-04-20

摘要/Abstract

摘要： 目的: 探讨五味子甲素(SchA)是否影响CYP3A底物-咪达唑仑在大鼠体内的代谢。方法: 不同剂量的五味子甲素或酮康唑75 mg/kg连续灌胃 3 d,采用单次十二指肠给药及腹股沟动脉插管,以CYP3A抑制剂(酮康唑)作为阳性对照,研究咪达唑仑在大鼠体内的代谢。高效液相色谱法(HPLC)测定血浆中咪达唑仑及其代谢物的浓度。结果: 口服不同药物后咪达唑仑的主要药动学参数为:AUC_(0-t)(mg·L^-1·h)分别为:(1.08±0.29) (阴性对照)、(1.58±0.58) (SchA 8 mg/kg)、(2.02±1.29)(SchA 16 mg/kg)、(2.22±1.25) (SchA 32 mg/kg)、(3.34±2.25)(酮康唑 75 mg/kg);C_max(mg/L)分别为:(1.6±0.6) (阴性对照)、(1.8±0.8) (SchA 8 mg/kg)、(2.2±1.2 )(SchA 16 mg/kg)、(2.2±0.7) (SchA 32 mg/kg)、(2.9±1.1) (酮康唑 75 mg/kg)。1′-羟基咪达唑仑的主要药动学参数如下: AUC_(0-t) (mg·L^-1·h)分别为:(0.61±0.17)(阴性对照)、(0.40±0.15) (SchA 8 mg/kg)、(0.39±0.20)(SchA 16 mg/kg)、(0.40±0.14) (SchA 32 mg/kg)、(0.35±0.09 )(酮康唑 75mg/kg);C_max (mg/L)分别为:(0.54±0.13) (阴性对照)、(0.42±0.15)(SchA 8 mg/kg)、(0.39±0.16)(SchA 16 mg/kg)、(0.36±0.16)(SchA 32 mg/kg)、(0.35±0.12) (酮康唑 75 mg/kg)。结论: 结果表明,五味子甲素可以显著抑制咪达唑仑的代谢。

关键词: 五味子甲素, 咪达唑仑, 1′-羟基咪达唑仑, 药动学, CYP3A4, HPLC法

Abstract: AIM: To evaluate whether Schisandrin A (SchA) can modify the pharmacokinetic profiles CYP3A substrates-midazolam in male rats. METHODS: The rats were intragastric administrated with varied dose SchA or 75 mg/kg ketoconazole for 3 consecutive days.Using of single-pass duodenum perfusion and inguinal artery -canulated rats (in vivo), midazolam metabolism was studied under chemical inhibition of CYP3A (ketoconazole) as positive control. Plasma concentrations of midazolam and related metabolites were analyzed by high performance liquid chromatography (HPLC). RESULTS: The pharmacokinetic parameters of midazolam after coadministration with SchA were as follows: AUC_(0-t) (mg·L^-1·h): (1.08±0.29) (negative control) and (1.58±0.58)(SchA 8 mg/kg) and (2.02±1.29) (SchA 16 mg/kg) and (2.22±1.25) (SchA 32 mg/kg) and 3.34±2.25 (ketoconazole 75 mg/kg);C_max (mg/L): (1.6±0.6) (negative control) and (1.8±0.8) (SchA 8 mg/kg) and (2.2±1.2) (SchA 16 mg/kg) and (2.2±0.7)(SchA 32 mg/kg) and (2.9±1.1) (ketoconazole 75 mg/kg).The pharmacokinetic parameters of 1′-hydroxy midazolam after coadministration with SchA were as follows: AUC_(0-t) (mg·L^-1·h): (0.61±0.17) (negative control) and (0.40±0.15) (SchA 8 mg/kg) and (0.39±0.20) (SchA 16 mg/kg) and (0.40±0.14) (SchA 32 mg/kg) and (0.35±0.09) (ketoconazole 75 mg/kg); C_max (mg/L): (0.54±0.13) (negative control) and (0.42±0.15)(SchA 8 mg/kg) and (0.39±0.20) (SchA 16 mg/kg) and (0.36±0.16) (SchA 32 mg/kg) and (0.35±0.12) (ketoconazole 75 mg/kg). CONCLUSION: The current results provide direct and explicit evidence that the metabolism of midazolam (a CYP3A substrate) is controlled by SchA in comparison with vehicle-treated rats.

Key words: Schisandrin A, Midazolam, 1'-hydroxy midazolam, Pharmacokinetics, CYP3A, HPLC method

中图分类号:

R969.1

辛华雯, 李维亮, 吴笑春, 李罄, 余爱荣. 五味子甲素对大鼠咪达唑仑及其代谢物1′-羟基咪达唑仑药动学影响[J]. 中国临床药理学与治疗学, 2012, 17(3): 245-250.

XIN Hua-wen, LI Wei-liang, WU Xiao-chun, LI Qing, YU Ai-rong. Effects of Schisandrin A on pharmacokinetics of midazolam and its metabolite in rats[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2012, 17(3): 245-250.

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