乙烷硒啉的临床药物动力学和代谢转化特点研究

目的研究肿瘤患者口服乙烷硒啉(1,2-[bis(1,2Benzisoselenazolone-3(2H)-ketone)]ethane,BBSKE)后的药物动力学及体内代谢转化特征。方法3例肿瘤患者单次口服给药剂量为600mg.d-1,采集各个时间点的血浆样品及尿样,用液相色谱-串联四极杆质谱(LC/ESI-MS/MS)联用技术测定血浆样品中BBSKE的含量,用液相色谱-电喷雾离子阱质谱(LC-ESI/MSn)联用技术对尿及血浆中的代谢产物进行分析鉴定。结果得到了BBSKE在血浆中的药时曲线图及主要的药物动力学参数。在尿中共发现了6个BBSKE的氧化、甲基化、葡萄糖醛酸化代谢产物,在血浆中共发现了2个BBSKE的氧化、葡萄糖醛酸化代谢产物。结论BBSKE的血药浓度较低,表观分布容积大。氧化、甲基化、葡萄糖醛酸化反应是BBSKE在人体内的3种重要代谢途径。

Clinical pharmacokinetics and metabolites investigation of BBSKE with LC-MS/MS assay

Aim To investigate the clinical pharmacokinetics and metabolites of 1,2-[bis(1,2-Benzisoselenazolone-3(2H)-ketone)] ethane(BBSKE)after oral administration of BBSKE.Methods Plasma samples and urine samples were collected from 3 tumor patients who were received a single oral administration of a 600 mg·d-1 dose of BBSKE.The plasma concentration of BBSKE was determined by liquid chromatography and tandem electrospray ionization triple-quadrupole mass spectrometry(LC/ESI-MS/MS).Both samples were analyzed by liquid chromatography and tandem electrospray ionization ion trap mass spectrometry(LC-ESI/MSn)to identificate metabolites.Results The AUC and main pharmacokinetic parameter were obtained.A total of 6 metabolites in urine and 2 metabolites in plasma were discovered,including oxidized,methylated,glucuronidated metabolites.Conclusions These results suggest that the plasma concentration of BBSKE is low,and the apparent volume of distribution of BBSKE is large.Oxidation,methylation and glucuronidation are three important metabolic pathways of BBSKE in human.