达沙替尼与槲皮素在大鼠体内药动学相互作用特征

Study on the pharmacokinetic interaction between dasatinib and quercetin in rats

目的:探讨达沙替尼与槲皮素联用后在大鼠体内药动学相互作用特征。方法:将大鼠随机分为3组,分别灌胃给药达沙替尼3.5 mg·kg^(-1)、槲皮素35 mg·kg^(-1)、达沙替尼3.5 mg·kg^(-1)+槲皮素35 mg·kg^(-1),连续给药14 d,于第15天给药后不同时间点眼眶采血,离心获取上层血浆。采用酶解法处理血浆样品,建立高效液相色谱串联质谱(HPLC-MS/MS)法同时检测血浆中的达沙替尼与槲皮素,描绘平均血药浓度-时间曲线,通过DAS 3.2.2软件对药动学参数进行分析。结果:达沙替尼单用与联用状态下主要药动学参数如下,AUC_(0-t):(0.28±0.035),(0.49±0.051)μg·h·mL^(-1);AUC_(0-∞):(0.29±0.035),(0.51±0.047)μg·h·mL^(-1);MRT_(0-t):(7.74±0.31),(7.44±0.25) h;MRT_(0-∞):(8.40±0.73),(7.99±0.58) h;t_(1/2):(4.32±0.80),(4.12±0.69) h;C_(max):(26.6±2.20),(46.76±4.74) ng·mL^(-1)。槲皮素单用与联用状态下主要药动学参数如下AUC_(0-t):(45.76±6.34),(60.15±6.72)μg·h·mL^(-1);AUC_(0-∞):(70.79±9.85),(95.06±1.46)μg·h·mL^(-1);MRT_(0-t):(19.12±0.78),(18.19±0.87) h;MRT_(0-∞):(46.55±4.23),(48.10±6.96) h;t_(1/2):(33.55±3.77),(36.04±4.67) h;C_(max):(1 964.89±144.09),(3 435.27±263.87) ng·mL^(-1)。结论:与单用相比,达沙替尼与槲皮素联用后,两药的AUC_(0-t)、AUC_(0-∞)、C_(max)显著增加(P<0.01),在血浆中暴露量增大,且连续给药的方式使槲皮素出现蓄积现象,临床用药时应根据二者的治疗窗合理安排给药方案。

OBJECTIVE To explore the pharmacokinetic characteristics of dasatinib combined with quercetin in rats.METHODS Rats were randomly divided into three groups,and given dasatinib 3.5 mg·kg^(-1),quercetin 35 mg·kg^(-1),dasatinib 3.5 mg·kg^(-1) + quercetin 35 mg·kg^(-1) for 14 days,respectively.Blood was collected from orbit at different time points after administration on the 15th day,and upper plasma was obtained by centrifugation.A high performance liquid chromatography tandem mass spectrometry(HPLC-MS/MS) method was established for the determination of dasatinib and quercetin in plasma,the average blood concentration-time curve was drawn and the pharmacokinetic parameters were analyzed by DAS 3.2.2 software.RESULTS The pharmacokinetic parameters of dasatinib in single and combined use were as follows:AUC_(0-t) of(0.28±0.035) and(0.49±0.051) μg·h·mL^(-1);AUC_(0-∞) of(0.29±0.035) and(0.51±0.047) μg·h·mL^(-1);MRT_(0-t) of(7.74±0.31) and(7.44±0.25) h;MRT_(0-∞) of(8.40±0.73) and(7.99±0.58) h;t_(1/2) of(4.32±0.80) and(4.12±0.69) h;C_(max) of(26.6±2.20) and(46.76±4.74) ng·mL^(-1).The pharmacokinetic parameters of quercetin in single and combined use were as follows:AUC_(0-t) of(45.76±6.34) and(60.15±6.72) μg·h·mL^(-1);AUC_(0-∞) of(70.79±9.85) and(95.06±1.46) μg·h·mL^(-1);MRT_(0-t) of(19.12±0.78) and(18.19±0.87) h;MRT_(0-∞) of(46.55±4.23) and(48.10±6.96) h;t_(1/2) of(33.55±3.77) and(36.04±4.67) h;C_(max) of(1 964.89±144.09) and(3 435.27±263.87) ng·mL^(-1).CONCLUSION Compared with those in the single use,the AUC_(0-t),AUC_(0-∞) and C_(max) of the two drugs increased significantly after the combination of dasatinib and quercetin,and the exposure of the two drugs in plasma both increases.The method of continuous administration makes quercetin accumulation.The administration plan should be reasonably arranged according to the treatment window of both drugs in clinical medication.