水飞蓟宾对奈韦拉平在大鼠体内药代动力学的影响

Effect of silibinin on the pharmacokinetics of nevirapine in rats

关键词:  奈韦拉平  水飞蓟宾  药代动力学  UPLC-MS/MS

Key words:  nevirapine  silibinin  pharmacokinetics  UPLC-MS/MS

摘要:

摘要：目的 探讨水飞蓟宾单次给药和多次给药对奈韦拉平在大鼠体内药代动力学的影响。方法 选用雄性SD大鼠30只，随机分为空白对照组、水飞蓟宾多次给药低剂量组（30 mg·kg-1·day-1）、水飞蓟宾多次给药高剂量组（100 mg·kg-1·day-1）、水飞蓟宾单次给药低剂量组（30 mg·kg-1）、水飞蓟宾单次给药高剂量组（100 mg·kg-1），给于奈韦拉平10mg·kg-1后采集血样测定大鼠血浆中奈韦拉平及其代谢产物的浓度。采用DAS计算各组药动学参数，并进行统计学分析。结果 与对照组相比，多次给予100mg·kg-1水飞蓟宾后，奈韦拉平的AUC增加了61.78%，Cmax升高了124.62%，清除率减少至64.11%；多次给予30mg·kg-1水飞蓟宾后，奈韦拉平的Cmax增加了84.85%；单次给予100mg·kg-1或30mg·kg-1水飞蓟宾后，奈韦拉平的Cmax分别增加了65.19%和32.12%。多次给予100mg·kg-1水飞蓟宾后，12-羟基-奈韦拉平的代谢比降低了31.5%；4-羧基-奈韦拉平的药代动力学参数未有显著变化。结论 水飞蓟宾能显著影响奈韦拉平在大鼠体内的药代动力学。临床上奈韦拉平与水飞蓟宾合用时，需考虑药物相互作用的影响。

Abstract:

ABSTRACT: OBJECTIVE To investigate the effect of single dose and multiple doses of silibinin on the pharmacokinetics of nevirapine in rats. METHODS Thirty male SD rats were randomly divided into control group, single dose (30 mg·kg-1 or 100 mg·kg-1) silibinin and multiple doses (30 mg·kg-1·day-1 or 100 mg·kg-1·day-1) silibinin group (n=6). Blood samples were collected to determine the concentration of nevirapine and its metabolites in rat plasma after an oral administration of 10 mg·kg-1 nevirapine. The kinetic parameters of nevirapine and its metabolites in each group were calculated by DAS and analyzed statistically. RESULTS Compared with the control group, multiple doses of 100 mg·kg-1·day-1 silibinin significantly increased the AUC of nevirapine by 61.78%, Cmax by 124.62% and decreased the clearance rate to 64.11%; multiple doses of 30 mg·kg-1·day-1 silibinin significantly increased the Cmax of nevirapine by 84.85%; a single dose of 100 mg·kg-1 or 30 mg·kg-1 silibinin significantly increased the Cmax of nevirapine by 65.19% and 32.12%, respectively. The metabolic ratio of 12-hydroxy-nervirapine was decreased by 31.5% by multiple doses of 100 mg·kg-1·day-1 silibinin where the pharmacokinetic parameters of 4-carboxyl-nervirapine remained unchanged. CONCLUSION Silibinin significantly affected the pharmacokinetics of nevirapine in rats. The drug-drug interaction should be considered when nevirapine and silibinin are concomitant.