氨丁三醇奥扎格雷注射液在健康人体的药代动力学研究

Pharmacokinetics of trometamol ozagrel injection in healthy Chinese volunteers

目的研究氨丁三醇奥扎格雷注射液在中国健康志愿者的单次及多次给药药代动力学特征并评价其与奥扎格雷钠注射液的相对生物利用度。方法研究采用单一剂量连续给药、双周期交叉试验设计,入组12例受试者随机静脉注射氨丁三醇奥扎格雷注射液(112 mg)或奥扎格雷钠注射液(80 mg),连续注射4d,每周期给药7次。用HPLC-MS/MS法测定给药后不同时间点奥扎格雷的血药浓度和尿样浓度。用Win Nonlin药代动力学软件计算药代动力学参数,用SPSS 18. 0软件进行统计分析。结果单次注射氨丁三醇奥扎格雷注射液112mg或奥扎格雷钠注射液80 mg的主要药代动力学参数如下:Cmax分别为(928. 41±104. 12)和(1025. 59±152. 35) ng·mL^(-1),t_(max)分别为(1. 75±0. 34)和(1. 83±0. 33) h,AUClast分别为(2029. 74±268. 98)和(2157. 34±308. 19)ng·mL^(-1)·h,AUC_(inf)分别为(2033. 40±269. 00)和(2160. 30±309. 00) ng·mL^(-1)·h,尿液中药物累积排泄量分别为(33. 66±11. 44)%和(36. 98±10. 51)%。单次给药后,受试制剂与参比制剂奥扎格雷的AUClast、AUC_(inf)、Cmax比值的90%置信区间分别为88. 20%～100. 69%,88. 16%～100. 64%和85. 47%～96. 77%。连续多次注射氨丁三醇奥扎格雷注射液112 mg或奥扎格雷钠注射液80 mg后的主要药代动力学参数如下:Cmax分别为(856. 95±108. 81)和(911. 24±128. 50)ng·mL^(-1),t_(max)分别为(1. 79±0. 26)和(1. 75±0. 26) h,AUClast分别为(1863. 29±264. 21)和(1915. 49±277. 41) ng·mL^(-1)·h,AUC_(inf)分别为(1866. 40±264. 00)和(1918. 60±278. 00) ng·mL^(-1)·h,尿液中药物累积排泄量为(33. 59±8. 60)%和(32. 66±8. 55)%,多次给药后,受试制剂与参比制剂奥扎格雷的AUC_(last)、AUC_(inf)、Cmax比值的90%置信区间分别为93. 08%～101. 68%,93. 10%～101. 65%和89. 99%～98. 52%。结论单次及多次给药后,与已上市的奥扎格雷钠注射液相比,氨丁三醇奥扎格雷注射液在体内的暴露量等效,且药物在人体内没有蓄积现象,药物安全性良好。

Objective To investigate the pharmacokinetics and relative bioavailability of trometamol ozagrel injection and ozagrel sodium injection by single-dose and multiple-dose intravenous administration in Chinese healthy volunteers.Methods This randomized,continuous single-dose,two-period,crossover study involved 12 healthy volunteers,who were randomly given trometamol ozagrel injection(112 mg)or ozagrel sodium injection(80 mg)by intravenous administration 7 times in 4 days per period.The concentration of ozagrel in plasma and urine were measured by high performance liquid chromatography/tandem massspectrum,the pharmacokinetic parameters were calculated using Win Nonlin software and the data analysis were analyzed using SPSS 18.0.Results The main pharmacokinetic parameters of trometamol ozagrel injection singly(112 mg)or ozagrel sodium injection singly(80 mg)were as follows: Cmaxwere(928.41±104.12)and(1025.59±152.35)ng·mL^-1,tmaxwere(1.75±0.34)and(1.83±0.33)h,AUClastwere(2029.74±268.98)and(2157.34±308.19)ng·m L^-1·h,AUCinfwere(2033.40±269.00)and(2160.30±309.00)ng·m L^-1·h,the cumulative excretion in the urine of ozagrel were(33.66±11.44)% and(36.98±10.51)%,the 90% confidence intervals(CIs)for the log-transformed ratios of AUClast,AUCinfand Cmaxwere 88.20%-100.69%,88.16%-100.64%,85.47%-96.77%.The main pharmacokinetic parameters of trometamol ozagrel injection or ozargrel sodium injection multiply constantly were as follows: Cmaxwere(856.95±108.81)and(911.24±128.50)ng·mL^-1,tmaxwere(1.79±0.26)and(1.75±0.26)h, AUClastwere(1863.29±264.21)and(1915.49±277.41)ng·mL^-1·h,AUCinf were(1866.40±264.00)and(1918.60±278.00)ng·mL^-1·h,the cumulative excretion in the urine of ozagrel were(33.59±8.60)% and(32.66±8.55)%,the 90% CIs for the log-transformed ratios of AUClast,AUCinfand Cmaxwere 93.08%-101.68%,93.10%-101.65%,89.99%-98.52%.Conclusion Compared with ozagrel sodium injection,the exposures of trometamol ozagrel injection after single and multiple doses were equivalence,there was no drug accumulation in body and the safety of trometamol ozagrel injection was good.