注射用灯盏花素对Beagle犬静脉给药的毒代动力学研究

Toxicokinetics of scutellarin in Beagle dogs

目的研究注射用灯盏花素在3个月静脉给药长期毒性试验过程中,药物在Beagle犬体内的代谢动力学特征,及其在体内的蓄积情况。方法在进行注射用灯盏花素对Beagle犬3个月静脉给药长期毒性试验过程中,分别于给药第一天和最后一天在不同的时间点采血,并用API 4000 LC-MS/MS仪检测血清中药物浓度。结果高、中和低剂量组Beagle犬首次给药后的平均AUC(0-t)值分别为56552.1、19200.5和2790.5μg/L×h;平均AUC(0-∞)值分别为56827.7、19256.1和2851.1μg/L×h;平均C max值分别为111620、61296和8813.67μg/L;平均t1/2值分别为4.41、3.60和2.27 h;首次给药的平均AUC(0-t)值与给药剂量呈正相关,相关系数为1,平均C max值与给药剂量不呈线性关系。高、中和低剂量组Beagle犬末次给药后的平均AUC(0-t)值分别为40956.7、29394.5和9492.4μg/L×h;平均AUC(0-∞)值分别为40959.5、29718.7和9898.2μg/L×h;平均C max值分别为106978、84000和30410μg/L;平均t1/2值分别为0.46、3.34和11.77 h。末次给药的平均AUC(0-t)值和平均C max值与给药剂量都不呈线性关系。结论注射用灯盏花素连续给药3个月,随着供试品给药时间延长,低剂量组血药浓度明显升高,低、高剂量组全身暴露量明显增加,因此认为本品长期给药存在一定的蓄积毒性危险。

Objective To research the pharmacokinetics features of scutellarin and the accumulation situation of its products in Beagle dogs, during three months intravenous injection with it. Methods During the long-term toxicity test of scutellarin injection on Beagle dogs, the blood was drawn at different time on the first day and the last day respectively, and then these samples were tested by API 4000 LC-MS/MS for drug blood concentration. Results The main pharmacokinetic parameters of first administration for high, middle and low dose groups as follows： AUC（0-t） average were 56552. 1, 19200. 5and 2790.5 μg/L x h, respectively; AUC（0-∞） average were 56827.7, 19256.1 and 2851. 1 μg/L x h, respectively; Cmax average were 111620, 61296 and 8813.67μg/L, respectively; t1/2 average were 4. 41, 3.60 and 2.27 h, respectively; AUC（0-t） average was positively correlated with administration dosage, and correlation coefficient was 1. The main pharmacokinetic parameters of last administration for high, middle and low dose groups as follows： AUC（0-t） average were 40956.7, 29394. 5 and 9492.4 μg/L x h, respectively ; AUC（0-∞ ） average were 40959. 5, 29718.7 and 9898.2 μg/L x h, respectively; Cm.x average were 106978, 84000 and 30410 μg/L, respectively; t1/2average were 0.46, 3.34 and 11.77 h, respectively. There didn＇ t exist the linear relationship between AUC（0-t） average, Cmax average and administration dosage. Conclusion Blood concentration of scutellarin in low dose group became higher obviously, and its systemic exposure concentration of low and high dose groups increased significantly. Therefore, it exists the risk of accumulation during long-term administration with scutellarin.