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目的研究盐酸伊伐布雷定在1个月经口给药长期毒性实验过程中,药物在Beagle犬体内的毒代动力学特征,及其在体内的蓄积情况。方法在进行盐酸伊伐布雷定对Beagle犬1个月经口给药长期毒性实验过程中,分别于给药第一天和最后一天在不同的时间点采血,并用HPLC测定血浆中药物浓度。结果高、中和低剂量组Beagle犬初次给药后的平均AUC0-t值分别为22.9、9.53和2.45 mg·h·L-1;平均AUC0-∞值分别为26.3、9.66和2.58 mg·h·L-1;平均ρmax值分别为9.19、4.72和1.91 mg·L-1;平均t1/2值分别为2.15、0.811和0.721 h。高、中和低剂量组Beagle犬末次给药后的平均AUC0-t值分别为30.8、11.3和3.02 mg·h·L-1;平均AUC0-∞值分别为44.7、11.6和3.45 mg·h·L-1;平均ρmax值分别为6.80、4.11和1.91 mg·L-1;平均t1/2值分别为4.16、1.04和1.06 h。结论盐酸伊伐布雷定在Beagle犬体内毒代动力学呈现线性动力学的特征,并且无明显的药物蓄积现象,无性别差异。
OBJECTIVE To study the toxicokinetic characteristics of drug in beagle dogs and its in vivo accumulation in the long-term oral toxicity test of 1 month by ivabradine hydrochloride. Methods During the long-term toxicity of oral administration of ivabradine hydrochloride to Beagle dogs, blood samples were collected at different time points on the first day and the last day respectively, and the plasma concentrations of the drugs were determined by HPLC. Results The mean AUC0-t values of Beagle dogs after initial administration were 22.9, 9.53 and 2.45 mg · h · L-1, respectively. The average AUC0-∞ values were 26.3, 9.66 and 2.58 mg · h · L-1; mean ρmax values were 9.19, 4.72 and 1.91 mg · L-1, respectively; mean t1 / 2 values were 2.15, 0.811 and 0.721 h, respectively. The average AUC0-t values of the high, medium and low dose Beagle dogs after the last administration were 30.8, 11.3 and 3.02 mg · h · L-1, respectively; mean AUC0-∞ values were 44.7, 11.6 and 3.45 mg · h · L-1; mean ρmax values were 6.80, 4.11 and 1.91 mg · L-1, respectively; mean t1 / 2 values were 4.16, 1.04 and 1.06 h, respectively. Conclusion The pharmacokinetics of ivabradine hydrochloride in Beagle dogs is characterized by linear kinetics and no significant drug accumulation, no gender differences.