维生素K_1软胶囊的人体药动学及生物等效性研究

Study on the pharmacokinetics and bioequivalence of vitamin K_1 soft capsules in healthy volunteers

目的：建立人血浆中维生素K1浓度的HPLC-APCI-MS测定方法，并评价维生素K1软胶囊的药动学特征及其与维生素K1片剂的人体生物等效性。方法：20名男性健康受试者随机分成2组，分别交叉口服受试制剂和参比制剂各10mg，采用HPLC-APCI-MS法测定人血浆中维生素K1的浓度，估算维生素K1的药动学参数及两种制剂的人体生物等效性。结果：血浆中维生素K1的最低定量限为0．3ng·mL^-1，在0．3-1000ng·mL^-1范围内线性关系良好，批内及批间精密度RSD均小于15％。受试制剂与参比制剂的各主要药动学参数：tmax分别为（5．5±0．8）h和（5．0±0．8）h，cmax分别为（210．1±86．7）ng·mL^-1和（194．8±60．6）ng·mL^-1，t1／2分别为（8．8±1．7）h和（8．7±2．1）h，用梯形法计算AUCo硼分别为（1032．6±204．6）ng·mL^-1和（1053．9±185．7）ng·mL^-1。两种制剂的主要药动学参数cmax，AUCo-48经对数转换后进行方差分析及双单侧t检验，并计算90％置信区间，表明两种制剂生物等效，相对生物利用度为（99．7±21．2）％。结论：两种制剂生物等效。

Objective：To establish an HPLC-APCI-MS method for the determination of vitamin K1 in human plasma and to evaluate the pharmacokinetics and bioequivalence of vitamin K1 soft capsule and vitamin K1 tablet in healthy volunteers. Methods： A 10 mg dose of the reference or test drug was given to 20 healthy male volun- teers in a randomized two-way crossover design and the plasma concentration of the drug was assayed by HPLC- MS. The main pharmacokinetic parameters and bioequivalence of the two formulations were evaluated. Results： The LOQ of the HPLC-APCI-MS method for vitamin K1 in plasma was 0.3ng·mL^-1 and the calibration curve was linear over the range of 0. 3 - 1000ng·mL^-1. The intra-and inter-run standard deviation was less than 15%. The t C tl/2, and AUCo-48 of the test and reference drugs were （5.5±0. 8） and （5.0±0. 8） h, （210.1±86.7） and （194.8±60.6） ng·mL^-l, （8.8±1.7） and （8.7±2.1） h, （1032.6±204.6） and （ 1053.9±185.7）ng·mL^-1, respectively. The relative bioavailability of the test product to the reference was 99.7±21.2%. Conclusion： The two formulations were bioequivalent.