两种盐酸阿考替胺水合物在Beagle犬体内的药动学

Pharmacokinetics of Two Forms of Acotiamide Hydrochloride Hydrate in Beagle Dogs

以盐酸阿考替胺三水合物为原料制备盐酸阿考替胺一水合物。以4只Beagle犬为模型动物,采用交叉给药方式分别口服给予(10 mg/kg)盐酸阿考替胺三水合物和一水合物胶囊,以静脉注射(2.5 mg/kg)三水合物溶液为参比,采用液相色谱-串联质谱法,以丁螺环酮为内标,测定Beagle犬血浆中阿考替胺的浓度,并计算盐酸阿考替胺的2种水合物胶囊在Beagle犬体内的药动学参数及生物利用度。结果表明,Beagle犬口服盐酸阿考替胺三水合物及一水合物胶囊后,AUC0→t为(3 613±788.7)和(2 904±910.3)h·ng·ml^(-1),t1/2为(1.36±0.17)和(1.33±0.44)h,MRT为(1.87±0.07)和(1.66±0.11)h,Beagle犬静脉给予三水合物溶液后的AUC_(0→t)为(2 949±497.9)h·ng·ml^(-1)、t_(1/2)为(1.15±0.13)h、MRT为(1.39±0.08)h。盐酸阿考替胺三水合物和一水合物胶囊在Beagle犬体内的口服生物利用度分别为(31.2±7.8)%和(27.6±11.3)%。

Acotiamide hydrochloride monohydrate was prepared from acotiamide hydrochloride trihydrate. Four Beagle dogs were orally administered acotiamide hydrochloride trihydrate and monohydrate capsules at a dose of 10 mg/kg respectively by cross-over design trial with intravenous injection of the trihydrate solution at a dose of 2.5 mg/kg as a reference. The acotiamide concentration in plasma was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with buspirone as internal standard. The pharmacokinetics and bioavailability of acotiamide in Beagle dogs after administering two hydrates of capsules orally were calculated respectively. The main pharmacokinetic parameters of the trihydrate capsules, the monohydrate capsules and the trihydrate solution were as follows: AUC0→t were (3 613±788.7),(2 904±910.3) and (2 949±497.9) h ·ng· ml^-1;t1/2 were (1.36±0.17),(1.33±0.44) and (1.15±0.13)h;MRT were (1.87±0.07),(1.66±0.11) and (1.39±0.08)h. The bioavailabilities of acotiamide hydrochloride trihydrate and monohydrate capsules in Beagle dogs were (31.2±7.8)% and (27.6±11.3)%, respectively.