托吡酯胶囊的药代动力学及生物等效性研究

Pharmacokinetics and Bioequivalence of Topiramate Capsule and Tablets in Healthy Volunteers

目的：建立高效液相色谱-质谱法（LC-MS）测定人血浆中托吡酯浓度,研究托吡酯胶囊与片剂在健康人体内的药代动力学过程,并评价两者的生物等效性。方法：用随机交叉给药方案对20名健康男性受试者分别给予单剂量口服托吡酯胶囊和托吡酯片（100 mg）,按时采集血样,提取处理后经LC-MS分析测定血浆中托吡酯浓度,并评价两种制剂的生物等效性。结果：托吡酯血浆标准样品在0.34~8.69μg/mL浓度范围内与峰面积线性关系良好（r=0.9993）,提取回收率为96.03%~104.27%,日内、日间RSD分别为3.72%±2.07%和4.33%±1.97%,相对标准偏差〈6.5%。口服试验和参比制剂后的药代动力学参数：Tmax为（1.48±0.35）h和（1.51±0.40）h,Cmax为（2 091.2±113.8）ng/mL和（2 125.6±123.5）ng/mL,t1/2为（31.49±4.52）h和（30.15±5.17）h,AUC0~96为（55 853±5 040）和（55 746±5 221）ng/（h·mL）;口服受试制剂和参比托吡酯制剂后的F0~96和F0~∞分别为103.19%±15.42%和102.58%±17.19%。结论：本文建立的LC-MS方法灵敏、准确、简便,适用于托吡酯的临床药代动力学研究,托吡酯胶囊与片剂具有生物等效性。

Objective： To establish a method for determining concentration of topiramate in human plasma by high performance liquid chromatography-mass spectrometry, study pharmacokinetic of topiramate capsules and tablets in healthy volunteers, and compare the hioequivalence with two preparations. Methods： Using random cross regimen given twenty healthy male volunteers a single oral dose of topiramate capsules and tablets （100 mg） ; blood samples were collected on time and extracted. Topiramate concentrations in plasma were determined by LC-MS. The pharmaeokinetie parameters and bioequivalence of two formulations were measured. Results： The calibration was linear within the range of 0. 34 - 8. 69 μg/mL （ r = 0. 9993 ）, and the relative good extraction recovery was 96.03% - 104.27%. The intra-day and inter-day RSDs were 3.72% ±2.07% and 4.33% ±1.97%, and the relative deviation was less than 6.5%. The main pharmaeokinetic parameters of topiramate by oral administration were as followed： Tmax were（ 1.48±0.35 ）and （1.51±0.40）hours, Cmax were （2,091.2±113.8） and （2,125.6±123.5） μg/mL, tl/2 were （31.49±4.52） and （30.15±5.17） hours, AUC0-96 were （55,853 ± 5,040） and （55,746± 5,221 ） μg/mL, for the tested and reference preparations of topiramate, respectively. The relative bioavailability F0_96 and F0-% were 103.19% ±15.42% and 102.58% ±17.19%. Conclusions： The method is sensitive, accurate and simple. It is suitable for the determination of clinical specimens of topiramate and clinical pbarmacokinetic study. The test topiramate capsules and reference topiramate tablets are bioequivalence.