S-奥拉西坦和奥拉西坦在Beagle犬体内的药动学对比研究

Pharmacokinetics comparison of S-Oxiracetam and Oxiracetam in Beagle dogs

目的比较Beagle犬口服S-奥拉西坦（S-ORT）和消旋奥拉西坦（ORT）后在体内的药动学差异。方法采用双交叉两周期实验设计,分别给予18只Beagle犬口服50、150、450 mg·kg-1S-ORT及ORT,采用HPLC-MS/MS法测定血浆中ORT的浓度,分别计算其药动学参数;采用Agilent Poroshell 120 SB-C18色谱柱,流动相为甲醇-水（30∶70,含10 mmol乙酸铵及0.1%甲酸）,内标为吡拉西坦,电喷雾离子源（ESI）,正离子模式,多反应离子监测（MRM）,监测离子为m/z 159.0→113.8（ORT）、m/z 143.1→98.0（内标）。结果 Beagle犬口服50、150、450 mg·kg-1S-ORT和ORT后,S-ORT、ORT的主要药动学参数：Cmax分别为42.78±15.29、115.38±71.38、183.24±43.03μg·m L-1和41.95±15.59、94.49±37.87、227.86±211.80μg·m L-1;Tmax分别为1.68±1.27、1.21±0.51、1.79±0.51 h和1.46±0.40、1.58±0.11、2.00±1.10 h;t1/2分别为1.60±0.34、2.45±0.88、3.74±0.74 h和1.53±0.35、2.18±0.46、2.90±0.73 h。结论 Beagle犬口服不同剂量的S-ORT、ORT后,Cmax、Tmax、t1/2、AUC0-t、AUC0-∞无显著性差异,主要药动学参数基本一致。

OBJECTIVE To compare the pharmacokinetic differences between S-Oxiracetam（ S-ORT） and Oxiracetam（ ORT）after being orally administrated in Beagles. METHODS By using a double-crossed two periodical experimental design,18 Beagles were orally administrated of S-ORT and ORT with the dosages at 50 mg·kg-1,150 mg·kg-1 and 450 mg·kg-1,respectively. LC-MS/MS was used to determine the concentrations of ORT in the plasma,then calculating the pharmacokinetic parameters for both S-ORT and ORT. The Agilent Poroshell 120 SB-C18 analytical column was used with the mobile phase of methanol-water（30∶70）,in which containing 10 mmol ammonium formate and 0. 1% formic acid. Piracetam was used as the internal standard（ IS）. Electrospray ionization source（ ESI） was operated in positive ion mode. The quantification was performed using multiple reaction monitoring（ MRM） mode with the transitions of m/z 159. 0→113. 8 for ORT and m/z 143. 1→98. 0 for the IS. RESULTS After Beagles were orally administrated with 50,150 and 450 mg·kg-1 S-ORT and ORT,the main pharmacokinetic parameters of S-ORT and ORT were as follows：Cmaxwas42. 78 ± 15. 29 μg·m L-1,115. 38 ±71. 38 μg·m L-1,183. 24 ±43. 03 μg·m L-1 and 41. 95 ± 15. 59 μg·m L-1,94. 49 ± 37. 87 μg·m L-1,227. 86 ± 211. 80 μg·m L-1 respectively;Tmaxwas 1. 68 ± 1. 27 h,1. 21 ± 0. 51 h,1. 79 ± 0. 51 h and 1. 46 ± 0. 40 h,2. 58 ± 0. 11 h,2. 00 ±1. 10 h,respectively;t1/2 was 1. 60 ± 0. 34 h,2. 45 ± 0. 88 h,3. 74 ± 0. 74 h and 1. 53 ± 0. 35 h,2. 18 ± 0. 46 h,2. 90 ± 0. 73 h,respectively.CONCLUSION After Beagles were orally administrated with 3 dosages of S-ORT and ORT,there were no significant differences between S-ORT and ORT in the C（max）,T（max）,t（1/2）,AUC（0-t） and AUC（0-∞）. Their main pharmacokinetic parameters have good consistency.