目的 利用固相萃取-高效液相色譜，建立測定人血漿中瑞格非尼及其代謝產(chǎn)物N-氧化瑞格非尼和去甲-N-氧化瑞格非尼的方法，研究其人體藥動力學(xué)。方法 采用固相萃取-高效液相色譜法進行檢測，以索拉非尼為內(nèi)標(biāo)，Oasis HLB型固相萃取柱（200 mg×6 mL）；流動相：0.5%磷酸二氫鉀溶液-乙腈（30∶70）；檢測波長：260 nm；體積流量：0.5 mL/min；柱溫：30℃；進樣量：5 μL。健康志愿者空腹條件下用50 mL溫水送服40、160 mg/片瑞格非尼片。利用DAS 2.1.1軟件對藥-時數(shù)據(jù)進行統(tǒng)計學(xué)分析，并得到主要藥動學(xué)數(shù)據(jù)。結(jié)果 瑞格非尼及其代謝產(chǎn)物N-氧化瑞格非尼和去甲-N-氧化瑞格非尼在10~10 000 ng/mL線性關(guān)系良好；檢測限（LOD）分別為0.67、0.72、0.57 ng/mL；定量限（LOQ）分別為1.98、2.32、1.61 ng/mL；得到瑞格非尼及其代謝產(chǎn)物N-氧化瑞格非尼和去甲-N-氧化瑞格非尼藥-時曲線和主要藥動學(xué)數(shù)據(jù)。40、160 mg/片規(guī)格瑞格非尼片中瑞格非尼的C_max、AUC_last、AUC_mf、t_1/2分別為（2 215.7±216.9）、（5 721.2±672.1）ng/mL，（13 772.9±10 231.1）、（51 182.3±43 219.2）ng·h/mL，（12 858.3±12 510.2）、（66 531.8±51 093.1）ng·h/mL，（6.58±1.31）、（13.12±4.23）h。結(jié)論 采用固相萃取-高效液相色譜法考察瑞格非尼片在健康志愿者體內(nèi)的藥動學(xué)研究具有操作簡便、可靠性高等優(yōu)點，對該藥的應(yīng)用具有重要意義。

Objective To establish a method for simultaneous determination of regorafenib and its metabolites N-oxidemetabolite and desmethyl N-oxide metabolite in human plasma by solid phase extraction-HPLC, and study pharmacokinetics of Regorafenib Tablets in health volunteer. Methods After plasma sample was performed, using sorafenib as internal standard, the determination was performed on Oasis HLB column (200 mm×6 mm), with 0.5% monopotassium phosphate-methanol (30:70) as mobile phase, the UV detection wavelength was 260 nm with flow rate as 0.5 mL/min. The column temperature was set at 40℃, and injection volume was 5 μL. Health volunteer were po administered with Regorafenib Tablets 40 and 160 mg/tablet under fasting conditions with 50 mL warm water. DAS 2.1.1 software was used to calculate the major pharmacokinetic parameters. Results The linear ranges for regorafenib and its metabolites N-oxidemetabolite and desmethyl-N-oxide metabolite were 10-10 000 ng/mL. LOD and LOQ were 0.67, 0.72, 0.57 ng/mL and 1.98, 2.32, and 1.61 ng/mL. Plasma concentration-time curves and major pharmacokinetic parameters of regorafenib and its metabolites N-oxidemetabolite and desmethyl N-oxide metabolite were obtained. Main pharmacokinetic parameters of regorafenib in Regorafenib Tablets with 40 and 160 mg/tablet were as following:C_max were (2 215.7 ±216.9) and (5 721.2 ±672.1) ng/mL; AUClas were (13 772.9 ±10 231.1) and (51 182.3 ±43 219.2) ng·h/mL; AUC_mf were (12 858.3 ±12 510.2) and (66 531.8 ±51 093.1) ng·h/mL; t_1/2 were (6.58 ±1.31) and (13.12 ±4.23) ng·h/mL. Conclusion The method is rapid and repeatable, and can be used for the determination of plasma concentration and pharmacokinetic study for Regorafenib Tablets in health volunteer, which is of great significance to the application of the drug.