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目的评价中国健康志愿者单次口服不同剂量替比夫定的药代动力学特征以及多次给药后的稳态血浆药代动力学。方法42名年龄在18～40岁的健康志愿者,男32名,女10名,随机分配到200、400、600、800mg 4个剂量组。其中600mg剂量组受试者接受单剂量和多剂量的研究。多剂量每日给药,持续8d。采用HPLC-MS/MS法测定给药前和给药后不同时间替比夫定的主血浆、尿液药物浓度,并据此计算药代动力学参数。结果在单次口服200、400、600、800mg片剂后,受试者的达峰时间分别为2．50、2．00、2．00h和2．50h；半衰期的平均值分别为(43．3±15．2)h、(49．1±14．4)h、(39．4±12．1)h和(46．7±20．8)h；血药达峰浓度平均值分别为(1 753．2±389．0)ng/ml、(2 586．7±871．4)ng/ml、(3 703．6±1 219．0)ng/ml和(3 454．6±953．9)ng/ml；曲线下面积的平均值分别为(12 843．2±2 925．6)ng·h ~(1·)ml~1、(22 948．9±5 721．0)ng·~(1·)ml~1、(26 440．5±8 938．1)ng·h ~(1·)ml~1以及(28 820．9±7 912．9)ng·h ~(1·)ml~1；血浆清除率(600mg)为(6 545．6±1 504．4)ml/h；多次给药后的稳态药代动力学研究结果显示,在600mg/d的给药剂量下,连续给药8d后,平均稳态药时曲线下面积为(26 123．9±7 196．3)ng·h ~(1·)ml~1,平均血药浓度为(1 088．5±299．8)ng/ml,血药达峰浓度和曲线下面积蓄积囚子分别为1．02±0．21和1．23±0．26。结论受试者口服替比夫定以后,吸收较为迅速,给药后的2～3h即达到峰值。在200mg至800mg剂量范围内,血浆中替比夫定的药代动力学参数均呈现出一定的规律。替比夫定在受试者体内有轻微蓄积。
Objective To evaluate the pharmacokinetics and pharmacokinetics of telbivudine at different doses in healthy volunteers in China and the steady-state plasma pharmacokinetics after repeated administrations. Methods Forty-two healthy volunteers aged from 18 to 40 years old, 32 males and 10 females, were randomly assigned to four doses of 200, 400, 600 and 800 mg. The 600 mg dose group received single and multiple dose studies. Multiple doses were given daily for 8 days. Pharmacokinetic parameters of telbivudine in plasma and urine before and after administration were determined by HPLC-MS / MS. Results After a single oral dose of 200, 400, 600 and 800 mg, the peak time of the subjects were 2.50, 2.00, 2.00 h and 2.50 h respectively; the mean half-lives were (43. 3 ± 15.2) h, (49.1 ± 14.4) h, (39.4 ± 12.1) h and (46.7 ± 20.8) h, respectively. The average peak plasma concentrations of (1 753.2 ± 389.0) ng / ml, (2 586.7 ± 871.4) ng / ml, (3 703.6 ± 1 219.0) ng / ml and (3 454.6 ± 953 .9) ng / ml; the average area under the curve was (12 843.2 ± 2 925.6) ng · h ~ (1 ·) ml ~ 1, (22 948.9 ± 5 721.0) ng · (1 · ml -1, (26 440.5 ± 8 938.1) ng · h -1 · ml -1 and (28 820.9 ± 7 912.9) ng · h -1 ·) Ml ~ 1; the plasma clearance rate (600mg) was (6 545.6 ± 1 504.4) ml / h; steady state pharmacokinetic study after multiple administrations showed that at 600mg / d The mean area under the curve of mean steady-state drug was (26 123.9 ± 7 196.3) ng · h ~ (1 ·) ml ~ 1 after 8 days of continuous administration and the average plasma concentration was (1 088 .5 ± 299.8) ng / ml, peak plasma concentration and area under the curve were 1.02 ± 0.21 and 1.23 ± 0.26, respectively. Conclusion After telbivudine was taken orally, the absorption of the drug was rapid and peaked at 2-3 h after administration. Pharmacokinetic parameters of telbivudine in plasma showed some regularity in the dose range of 200mg to 800mg. Telbivudine slightly accumulates in the subject.