雷诺嗪缓释片在比格犬体内的药代动力学

目的:研究雷诺嗪缓释片在比格犬体内的药物代谢动力学,并与参照制剂比较,为其是否具有缓释特征提供依据。方法:首先建立血浆中雷诺嗪浓度的液相色谱-串联质谱联用检测方法,并考察方法的专属性、准确度、日内日间精密度、回收率、线性范围等。采用随机对照试验设计,将12只比格犬随机分为A、B组,每组6只,分别服用1片雷诺嗪缓释片(500 mg/片)和1片参比制剂雷诺嗪片(500 mg/片),均于给药前和给药后不同时间点采集血样,用已建立的液质联用方法检测血样中雷诺嗪的血药浓度,计算2组比格犬的药代动力学参数。结果:受试组和参照组半衰期t1/2分别为13.3±8.3和2.36±0.92 h,峰浓度Cmax分别为923.9±340.5和3205±1314 ng/mL,达峰时间Tmax分别为1.6±0.38和0.88±0.14 h,曲线下面积AUC0~∞分别为6252.1±2860.3和9916±4305(ng·h)/mL,清除率Cl分别为11.3±9.8和6.39±3.95 L/(kg·h)。受试制剂雷诺嗪缓释片和参比制剂雷诺嗪片的药代特征和血药浓度-时间变化趋势明显不同,受试组血药浓度缓慢上升和下降,峰值较低;而参照组血药浓度峰值显著高于受试组,有明显的突释效应。结论:液质联用检测方法准确可靠,适合体内药代动力学研究;与参比制剂雷诺嗪片相比,受试制剂雷诺嗪缓释片符合缓释片的基本药代动力学特点。

Pharmacokinetic Studies on Ranolazine Extended-Release Tablets Ad ministered to Beagle Dogs

Objective： To study the pharmacokinetics behavior of ranolazine extended-release tablets and com- pared with that of ranolazine tablets administered to beagle dogs, and to provide the experimental evidence support ing characteristics of extended-release. Methods： An LC-MS/MS method for quantification of ranolazine in beagle dogs was established, then the specificity, accuracy, intra-day and inter-day precision, recovery and linear range were validated. In the randomized controlled study design, twelve beagle dogs were randomized divided into group A（tested group） and B（reference group）, each group had six dogs. One ranolazine extended-release tablet was ad- ministered to each dog in group A（500 mg/tablet） and one ranolazine tablet was administered to each dog in group B（500 mg/tablet）. Plasma samples were collected before administration and different time after administra- tion for group A and B. The established method was used to determine the concentration of ranolazine in plasma samples and pharmacokinetic parameters were calculated and compared within the two groups. Results： The half life time（tv2） of group A and B were 13.3±8.3 and 2.36±0.92 h, maximum concentration（Cmax） were 923.9±340.5 and 3205±1314 ng/mL, time to peak（Tin,x） were 1.6±0.38 and 0.88±0.14 h;area under the curve（AUCo-∞） were 6252.1±2860.3 and 9916±4305 （ng.h）/mL, clearance rate（C/） were 11.3±9.8 and 6.39±3.95 L/（h.kg）, respective ly. The tested ranolizne extended-release tablets had distinct difference in pharmaeokinetic characteristics and con centration-time profile compared to reference ranolazine tablets. The concentration of tested group（A） climbed anddeclined slowly, while the peak concentration Cn,~x of reference group（B） was much higher than tested group（A）, indicating an obvious effect of sudden release. Conclusion： The established LC-MS/MS method is suitable to study pharmacokinetics in vivo. Compared to reference preparation ranolazine tablet, the pharmacokinetics of tested preparation ranolazine extended-release tablet indicated the characteristics of extended-release.