酪氨酸激酶抑制药SHR115723的药效学及药动学

目的对SHR115723进行初步体外和体内药效学、药动学研究,并与舒尼替尼进行比较,以了解SHR115723新药开发的潜力。方法用磺酰罗丹明B蛋白染色法检测药物对人脐静脉内皮细胞体外生长的抑制作用,用裸小鼠异体移植入结肠癌HT-29模型检测药物体内的抗肿瘤作用,应用高效液相色谱-紫外检测法进行大鼠体内的药动学研究。结果SHR115723和舒尼替尼对人脐静脉内皮细胞增殖的IC_(50)分别为(1.3±s 0.3)和(0.78±0.23)μmol·L~(-1)。SHR115723和舒尼替尼对裸小鼠异体移植人结肠癌HT-29生长具有明显的抑制作用。SHR115723的AUC和c_(max)高于舒尼替尼,但V_d较小。结论SHR115723具有明显的抗肿瘤作用,具有一定的新药开发潜力。

Pharmacodynamics and pharmacokinetics of SHR115723,a novel tyrosine kinase inhibitor

AIM To evaluate the pharmacodynamics and pharmacokinetics of SHR115723 in comparison with those of sunitinib in vitro and in vivo,to determine the prospects of SHR115723 for new drug development. METHODS The growth inhibitory effects of the compounds on human umbilical vein endothelial cells (HUVEC)were determined by sulforhodamine B assay in vitro.Murine xenograft model of HT-29 human colon cancer was developed to evaluate the antitumor effects of the compounds in vivo.High performance liquid chromatography plus ultraviolet detector were used in the pharmacokinetics study of the compounds in rats. RESULTS The IC_(50)of the growth inhibitory effects for SHR115723 and sunitinib on HUVEC were(1.3±s 0.3) and(0.78±0.23)μmol·L~(-1),respectively.Significant growth inhibitory effects of SHR115723 and sunitinib on HT-29 tumor were observed in mice.The A UC and c_(max)of SHR115723 were better than those of sunitinib in rats, but SHR115723 had a smaller distribution volume than sunitinib.CONCLUSION SHR115723 has remarkable antitumor effects and better pharmacokinetics characteristics,and could be an attractive target for new drug development.