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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 the pharmacokinetics of single-dose and multi-dose oral trifluride capsules in healthy volunteers in China and provide a reference for clinical use in Chinese. Methods Forty healthy volunteers were randomly divided into 4 groups with 10 in each group, with half male and half female. The single dose of low, medium and high doses of the three groups were 300,600 and 900 mg; multiple doses of 600 mg, for 7 days. The adverse events were observed and the plasma concentration of trifluralin and its active metabolite 4-trifluoromethyl-4-trifluoromethylbenzoic acid (HTB) were simultaneously determined by HPLC. The pharmacokinetic parameters were calculated. Results Thirty (34.5 ± 2.2), (6.4 ± 2.1) and (11.4 ± 2.9) mg of trifloiclovir ρmax in plasma, · L-1 and AUC0-t were (6.1 ± 2.1), (10.2 ± 2.8) and (15.6 ± 3.9) mg · h · L -1, respectively. The ρmax of active metabolite HTB were (40.6 ± 7.0) (2 235.0 ± 537.5), (4 108.4 ± 1 366.1) and (6 018.8 ± 1 123.2) mg · h · L -1, respectively (P <0.01), 66.7 ± 10.5 and 103.6 ± 8.6 mg · L- ; After continuous administration of 600 mg, the ρ av of Triflubal and its active metabolite HTB were (0.6 ± 0.1) and (111.0 ± 18.0) mg · L -1, respectively, with AUCss of (15.5 ± 3.2) and (2664.4 ± 432.6) mg · h · L-1, and AUCss0-t were (14.7 ± 2.6) and (8 545.3 ± 1815.4) mg · h · L-1, respectively; t-test was performed on the major pharmacokinetic parameters of each dose group There were no significant differences in other parameters except for the difference of Vd in 900 mg group (P> 0.05). Conclusions After oral administration of Trifluralin capsules in Chinese population, the drug and active metabolite HTB showed a linear kinetic characteristic within the dose range of this study. The main pharmacokinetic parameters were non-sex difference. Trifluralin did not accumulate in the body, but the active metabolites HTB accumulation phenomenon exists, clinical medication should pay attention to the time interval.