盐酸西那卡塞片在糖尿病大鼠体内的药代动力学研究

Pharmacokinetic of cinacalcet hydrochloride tablets in diabetic rats

目的建立高效液相色谱-质谱法(HPLC-MS/MS)测定大鼠灌胃盐酸西那卡塞后血药浓度,分析盐酸西那卡塞片在糖尿病大鼠体内的药代动力学。方法从25只大鼠中随机抽取10只设为正常组;其余15只腹腔注射链脲佐菌素65 mg·kg^(-1)建造糖尿病模型,其中有11只建模成功大鼠设为模型组。建模后30 d,检测2组大鼠的生化指标及体重;2组大鼠灌胃盐酸西那卡塞10 mg·kg^(-1)后,以HPLC-MS/MS测定血药浓度,用WinNonlin软件计算药代动力学参数;蛋白质印迹法检测2组肝组织细胞色素P4503A1(CYP3A1)、P-糖蛋白(P-gp)蛋白表达量。结果正常组、模型组大鼠的体重分别为(375.26±42.13)和(254.10±26.87)g;这2组大鼠的空腹血糖分别为(5.67±0.69)和(24.51±5.39)mmol·L^(-1);这2组大鼠的三酰甘油分别为(1.52±0.19)和(10.37±2.05)mmol·L^(-1)。正常组、模型组1 h的血药浓度分别为(32.54±4.95)和(17.50±1.57)ng·mL^(-1);这2组大鼠1.5 h的血药浓度分别为(24.51±3.68)和(19.03±1.62)ng·mL^(-1);这2组大鼠的Cmax分别为(38.50±4.56)和(22.90±3.32)ng·mL^(-1);这2组大鼠的表观分布容积(Vd)分别为(15.02±1.25)和(18.33±1.65)L·kg^(-1);这2组大鼠的肝组织CYP3A1蛋白表达量分别为0.42±0.05和0.68±0.07;这2组大鼠的P-gp蛋白表达量分别为0.21±0.03和0.49±0.05。上述指标:模型组与正常组比较,差异均有统计学意义(均P<0.05)。结论糖尿病大鼠机体中盐酸西那卡塞药代动力学发生了一定变化,临床需注意该药在糖尿病患者中合理、安全用药问题。

Objective To analyze the pharmacokinetics of cinacalcet hydrochloride tablets in diabetic rats,high performance liquid chromatography-mass spectrometry(HPLC-MS/MS)method was established to determine the plasma concentration of cinacalcet hydrochloride in rats after intragastric administration.Methods Ten of 25 rats were randomly selected as normal group;the remaining 15 rats were intraperitoneally injected with 65 mg·kg^(-1)of streptozotocin to construct a diabetes model,and 11 successfully modeled rats were set as model group.The time at the 30 d after modeling,the biochemical indicators and body mass of normal group and model group were checked.HPLC-MS/MS method was used to determine the plasma concentration of cinacalcet hydrochloride 10 mg·kg^(-1)after intragastric administration in the 2 groups.The WinNonlin software was used to calculate the pharmacokinetic parameters.Western blot method was used to detect the relative expression of cytochrome P4503 A1(CYP3 A1)and P-glycoprotein(P-gp)protein in liver tissues of the two groups.Results The body weights of normal group and model group were(375.26±42.13)and(254.10±26.87)g;the fasting blood glucose of the two groups were(5.67±0.69)and(24.51±5.39)mmol·L^(-1);the triacylglycerol of the two groups were(1.52±0.19),(10.37±2.05)mmol·L^(-1);the 1-h plasma concentration of the two groups were(32.54±4.95)and(17.50±1.57)ng·mL^(-1);the 1.5-h plasma concentration of the two groups were(24.51±3.68)and(19.03±1.62)ng·mL^(-1);the Cm ax of the two groups were(38.50±4.56)and(22.90±3.32)ng·mL^(-1);the apparent volume of distribution(Vd)of the two groups were(15.02±1.25)and(18.33±1.65)L·kg^(-1);the expression of CYP3 A1 protein of the two groups were 0.42±0.05 and 0.68±0.07,respectively;the expression of P-gp protein of the two groups were 0.21±0.03 and 0.49±0.05,respectively.The above indicators:the differences between the model group and the normal group were statistically significant(all P<0.05).Conclusion The pharmacokinetics of cinacalcet hydrochloride in the body of diabetic rats has changed to a certain extent,and clinical attention should be paid to the rational and safe use of this drug in diabetic patients.