三氟柳胶囊在中国健康志愿者体内的药动学研究

Study on pharmacokinetics of triflusal capsules in Chinese healthy volunteers

目的研究中国健康志愿者单剂量和多剂量口服三氟柳胶囊的药动学特征,为中国人临床用药提供参考依据。方法健康志愿者40名,随机分为4组,每组10人,男女各半。单次给药的低、中、高3组给药剂量分别为300、600和900 mg;多次给药组每次给药600 mg,连续7 d。观察不良事件,HPLC法同时测定血浆中三氟柳及其活性代谢物4-三氟甲基水杨酸(2-hydroxy-4-trifluoromethyl benzoic acid,HTB)的质量浓度,计算药动学参数。结果 30名受试者分别单次口服三氟柳胶囊低、中、高3个剂量后,血浆中三氟柳ρmax分别为(5.3±2.2)、(6.4±2.1)和(11.4±2.9)mg·L-1,AUC0-t分别为(6.1±2.1)、(10.2±2.8)和(15.6±3.9)mg·h·L-1;活性代谢物HTB的ρmax分别为(40.6±7.0)、(66.7±10.5)和(103.6±8.6)mg·L-1,AUC0-t分别为(2 235.0±537.5)、(4 108.4±1 366.1)和(6 018.8±1 123.2)mg·h·L-1;连续给药600 mg后,三氟柳和活性代谢物HTB的ρav分别为(0.6±0.1)和(111.0±18.0)mg·L-1,AUCss分别为(15.5±3.2)和(2 664.4±432.6)mg·h·L-1,AUCss0-t分别为(14.7±2.6)和(8 545.3±1 815.4)mg·h·L-1;对各剂量组主要药动学参数性别间进行t检验,除900 mg组Vd性别差异外,其他参数均无显著性差异(P>0.05)。结论中国人群口服三氟柳胶囊后,药物和活性代谢物HTB在本研究剂量范围内呈线性动力学特征,主要药动学参数无性别差异;三氟柳在体内无蓄积,但其活性代谢物HTB却存在蓄积现象,临床用药时应注意给药时间间隔。

Objective To study pharmacokinetics profile of Chinese healthy volunteers after a single dose and multiple-dose oral triflusal capsules. Methods Forty healthy volunteers w ere randomly divided into four groups（ n = 10）,half and half for men and w omen respectively. Single-dose group,including low dose,middle dose and high dose groups,w ere administered 300,600 and 900 mg of the medicine,respectively. Multiple dose group w ere administered 600 mg for 7 d. The adverse effects w ere observed,and HPLC method w as used for the simultaneous determination of the plasma concentration of triflusal and its active metabolites（ HTB）. The pharmacokinetic parameters were calculated. Results Thirty subjects of single oral groups were administered the triflusal capsules of 300,600 and 900 mg,the ρmaxof triflusal w ere（ 5. 3 ± 2. 2）,（ 6. 4 ± 2. 1） and（ 11. 4 ± 2. 9） mg·L- 1; AUC0-tw ere（ 6. 1 ± 2. 1）,（ 10. 2 ± 2. 8） and（ 15. 6 ± 3. 9） mg·h·L- 1, respectively. The ρmaxof active metabolite HTB were（ 40. 6 ± 7. 0）,（ 66. 7 ± 10. 5） and（ 103. 6 ± 8. 6） mg·L- 1; AUC0-tw ere（ 2 235. 0 ± 537. 5）,（ 4 108. 4 ± 1 366. 1） and（ 6 018. 8 ± 1 123. 2） mg·h·L- 1. After continuous administration of 600 mg for 7 d,triflusal and HTB ρavw ere（ 0. 6 ± 0. 1） and（ 111. 0 ± 18. 0） mg·L- 1, respectively; AUCssw ere（ 15. 5 ± 3. 2） mg·h·L- 1and（ 2 664. 4 ± 432. 6） mg·h·L- 1; AUCss0-tw ere（ 14. 7 ± 2. 6） mg·h·L- 1and（ 8 545. 3 ± 1 815. 4） mg·h·L- 1. Vdgender difference w as found only for 900 mg group,and the other pharmacokinetics parameters for triflusal or HTB show ed nosignificant sex-dependent difference（ P 0. 05）. Conclusions The pharmacokinetics of triflusal and active metabolite HTB in Chinese healthy volunteers exhibit linear behavior in dose range of 300-900 mg,the main pharmacokinetic parameters have no gender differences; triflusal has no accumulation in the body,but HTB exists accumulation phenomenon,w e should pay attention to the time interval w hen continuous administration drugs.