Abstract：
Palbociclib and ribociclib an orally bioavailable, potent cyclin-dependent kinase 4/6 inhibitors, with low oral bioavailability due to substrate specificity towards CYP3A and P-glycoprotein. Thus, current research aims to examine the effect of a bioenhancer (naringin), on oral pharmacokinetics of palbociclib and ribociclib. Naringin\'s affinity for CYP3A4 and P-glycoprotein was studied using molecular docking; its impact on palbociclib/ribociclib CYP3A metabolism and P-glycoprotein-mediated efflux was examined using in vitro preclinical models; and its oral pharmacokinetics in rats were assessed following oral administration of palbociclib/ribociclib in presence of naringin (50 and 100 mg/kg). Naringin binds optimally to both proteins with the highest net binding energy of - 1477.23 and - 1607.47 kcal/mol, respectively. The microsomal intrinsic clearance of palbociclib and ribociclib was noticeably reduced by naringin (5-100 µM), by 3.0 and 2.46-folds, respectively. Similarly, naringin had considerable impact on the intestinal transport and efflux of both drugs. The pre-treatment with 100 mg/kg naringin increased significantly (p < 0.05) the oral exposure of palbociclib (2.0-fold) and ribociclib (1.95-fold). Naringin\'s concurrent administration of palbociclib and ribociclib increased their oral bioavailability due to its dual inhibitory effect on CYP3A4 and P-glycoprotein; thus, concurrent naringin administration may represent an innovative strategy for enhancing bioavailability of cyclin-dependent kinase inhibitors.
摘要：
Palbociclib和ribociclib口服生物可利用，有效的细胞周期蛋白依赖性激酶4/6抑制剂，由于对CYP3A和P-糖蛋白的底物特异性，口服生物利用度较低。因此，目前的研究旨在研究生物增强剂(柚皮苷)的作用，帕博西尼和瑞博西尼的口服药物动力学。使用分子对接研究了柚皮苷对CYP3A4和P-糖蛋白的亲和力；使用体外临床前模型检查了其对palbociclib/ribociclibCYP3A代谢和P-糖蛋白介导的外排的影响；在存在柚皮苷（50和100mg/kg）的情况下口服palbociclib/ribociclib后评估了其在大鼠中的口服药代动力学。柚皮苷最佳结合两种蛋白质，最高净结合能为-1477.23和-1607.47kcal/mol，分别。柚皮苷（5-100µM）明显降低了palbociclib和ribociclib的微粒体内在清除率，3.0和2.46倍，分别。同样，柚皮苷对两种药物的肠道运输和外排都有相当大的影响。用100mg/kg柚皮苷预处理显著增加(p<0.05)帕博西尼(2.0倍)和瑞博西尼(1.95倍)的口服暴露。柚皮苷同时服用帕博西尼和瑞博西尼，由于其对CYP3A4和P-糖蛋白的双重抑制作用，增加了其口服生物利用度；因此，同时给予柚皮苷可能是提高细胞周期蛋白依赖性激酶抑制剂生物利用度的创新策略。
