双靶标新药YL-0919在比格犬体内的药代动力学研究

Pharmacokinetics of YL-0919 a Novel Dual-acting Antidepressant in Beagle Dogs

目的研究5-HT1A受体激动和5-HT重摄取抑制双靶标新药YL-0919在比格犬体内多次给药的药代动力学。方法比格犬按1.5 mg.kg-1剂量灌胃给药,第1天和第5天各给药1次,第2～4天每天给药2次。采用LC-MS/MS法测定血浆中YL-0919浓度,用DAS 2.0软件计算药动学参数。结果首次和末次口服YL-0919(1.5 mg·kg-1)后,主要药代动力学参数为:Cmax分别为(287.73±106.50)和(220.07±58.90)ng·ml-1;tmax分别为(1.10±0.55)和(0.95±0.67)h;t1/2z分别为(3.28±0.85)和(3.02±1.20)h;MRT(0～24)分别为(4.16±0.59)和(3.81±1.22)h;AUC(0～24)分别为(1242.10±462.27)和(922.29±345.29)ng·h·ml-1;AUC(0～∞)分别为(1251.23±464.03)和(938.57±350.30)ng·h·ml-1;CLz/F分别为(1.41±0.74)和(1.95±1.23)L·h-1·kg-1;Vz/F分别为(6.43±2.79)和(7.11±1.90)L·kg-1。经配对t检验,多次给药达稳态后除AUC(0～24)和AUC(0～∞)降低外,其余药动学参数差异均无统计学意义。结论 YL-0919在比格犬体内多次给药后无明显蓄积作用。

Objective To study the pharmacokinetics of YL-0919,a novel dual-acting antidepressant with 5-HT1A receptor agonist and serotonin reuptake inhibitor in beagle dogs after multiple-dose oral administration.Methods YL-0919 was given as a multiple oral dose of 1.5 mg · kg-1 once daily on day 1 and 5,and twice a day from day 2 to day 4 to five beagle dogs.The plasma concentration of YL-0919 was determined by LC-MS/MS.The main pharmacokinetic parameters were calculated by DAS 2.0 software.Results The main pharmacokinetic parameters after the first and last oral dose were as follows： Cmax were（287.73±106.50） and（220.07±58.90） ng · ml-1,tmax were（1.10±0.55） and（0.95±0.67） h,t1/2z were（3.28±0.85） and（3.02±1.20） h,MRT（0-24） were（4.16±0.59） and（3.81±1.22） h,AUC（0-24） were（1242.10±462.27） and（922.29±345.29） ng·h · ml-1,AUC（0-∞） were（1251.23±464.03） and（938.57±350.30） ng·h · ml-1,CLz/F were（1.41±0.74） and（1.95±1.23） L · h-1 · kg-1,Vz/F were（6.43±2.79） and（7.11±1.90） L · kg-1,respectively.There was no significant difference between the two groups of pharmacokinetic parameters except for AUC（0-24） and AUC（0-∞） analyzed by t-test.Conclusion There is no obvious accumulation after YL-0919 multiple-dose oral administration in beagle dogs.