达托霉素血浆浓度的UPLC-MS/MS法测定及其在重症患者体内药代动力学  

Determination of daptomycin by UPLC-MS/MS and its pharmacokinetic evaluation in critically ill patients

作　　者：胡琳璘 郭楠[2] 张学丽[1] 邵华[1] 

机构地区：[1]东南大学附属中大医院药学部,南京210009 [2]中国药科大学药学院,南京210009

出　　处：《中国药科大学学报》2015年第6期700-706,共7页Journal of China Pharmaceutical University

基　　金：南京药学会-常州四药医院药学科研基金资助项目(No.2015YX004)~~

摘　　要：建立测定血浆和置换液中达托霉素的高通量UPLC-MS/MS方法,采用Kinetex C_（18）色谱柱（50 mm×2.1 mm1.7μm）,柱温45℃,流动相为含0.1%甲酸水溶液-乙腈,流速0.4 mL/min,电喷雾离子化正离子扫描模式下,达托霉素m/z810.9→159.1;内标来曲哩m/z 286.2→217.2,分析时长2.5min。达托霉素在血浆（1~200μg/mL）和置换液（0.005~20μg/mL）中均呈现良好的线性关系,日内及日间精密度、准确度、稳定性等均符合生物样品测定要求。静脉滴注6mg/kg达托霉素在接受持续肾脏替代治疗（CRRT）治疗的感染性休克患者体内的C_（max）和AUC_（0-24）明显低于健康受试者,下降比例分别为50%和60%,未达到预期的杀菌效果。这可能与感染性休克患者毛细血管通透性增加联合间隙水肿,从而使药物的分布容积增加有关,此外,肾脏替代治疗模式可体外滤过约16%的达托霉素,导致剂量不足和感染治疗不彻底。研究结果推荐在接受CRRT治疗的感染性休克患者中使用达托霉素应适当增加剂量,且须对该类患者进行达托霉素治疗药物浓度监测。A sensitive, selective and simple liquid chromatography tandem mass spectrometry （UPLC-MS/MS） method was developed for determining of daptomycinin human plasma and effluent. The analyte was extracted from plasma samples by SPE method, separated through a Phenomenex Kinetex Cls column （50 mm× 2. 1 mm, 1.7 μm） using isocratic mobile phase consisting of 0. 1% formic acid-acetonitile（75 ： 25）, and analyzed by elec- tro-spray ionization （ESI）. The precursor to product ion transitions of m/z 810.9→159.1 and m/z 286.2→ 217.2 were used to measure daptomycinand the internal standard, respectively. The method was validated over a concentration range （ plasma： 1-200 μg/mL, effulent： 0. 005-20 μg/mL）. The intra- and inter-day precision values were less than 10% and accuracy values 90% -110%. The stability of daptomycinin human plasma and effluent under different storage conditions met the requirements of bioanalytical method. The concentration of daptomycin is significant lower in the septic shock patient, when give a dose of 6 mg/kg, theCmax and AUC0-24 h of steady state decreased by 50% and 60% respectively; the increase in capillary permeability and interstitial oedema during sepsis and septic shock may enhance drug distribution. By the way, daptomycin can be cleared via continuous veno-venous hemofihration （CVVH） for nearly 16%. In summary, on the treatment of continuous renal replace- ment therapy （CRRT） in patients with septic shock with daptomycin therapy, the suggested dose should beincreased, and the drug monitoring should be carried on.

关 键 词：达托霉素 UPLC-MS/MS法 持续肾脏替代治疗 感染性休克患者 药代动力学 

分 类 号：R969.1[医药卫生—药理学]