Objective: To establish an LC-MS/MS method for determining the concentration of tazobactan in human plasma, The pharmacokinetic characteristics of tazobactan single prescription (0.50 g) and the compound preparation (1∶6, 1∶4 and 1∶3) combined with cicotaxime sodiumwere investigated in healthy subjects after single/repeated administration, so as to provide reference for the safety and application of its clinical formulation. Methods: Plasma samples were processed by protein precipitation on a Waters Symmetry C18 (50 mm×2.1 mm, 3.5 μm) column at 35 ℃ with an auto sampler temperature of 4 ℃. The mobile phase was methanol-0.15% formic acid and 0.3% ammonia water (38∶62). The flow rate was 0.3 mL·min-1. In multistage reactive anion (MRM) mode, tazobactam and cefradine (internal standard) ions were m/z 298.80→138.00 and m/z 347.80→303.70.the established analytical method was used,the concentrations of tazobactam in plasma samples of 24 subjects who received intravenous tazobactam monotherapy and compound preparations of different proportions were determined at each time point after administration,and the main pharmacokinetic parameters obtained were calculated and analyzed. Results: The linear relationship of tazobactan in plasma was well within the range of 0.200-50.0 μg·mL-1 (r2=0.994 8), the lower limit of quantitation was 0.20 μg·mL-1, and the intra-day and inter-day precisions RSD was less than 15%. The recoveries rate ranged from 75.4%-81.0%, and matrix effect ranged from 91.8%-95.6%. The pharmacokinetic parameters Cmax and AUC0-t of tazobactam in the three dose groups increased with the increase of dose, and Cmax showed a linear increase, while AUC0-t and AUC0-∞shows a nonlinear increase. Conclusion: The LC-MS/MS method established is very simple, accurate and sensitive, pharmacokinetics studies of single/compound formulations and single/repeated administration indicates that tazobactan had no accumulation in human body. The study could be provided to a technical and theoretical support for concentration detection in human plasma and clinical formula application.
[1] 刘文, 查王健, 黄茂. 注射用头孢噻肟钠/他唑巴坦钠(6∶1)临床耐受性研究[J].药学与临床研究, 2011, 19(3):204
LIU W, ZHA WJ, HUANG M. Tolerance of intravenously administered cefotaxime sodium/tazobactam sodium (6:1) in a phase I study [J].Pharm Clin Res, 2011, 19(3):204
[2] 陈苏婉, 张守钗, 王晓娟, 等. 不同配比头孢噻肟钠/他唑巴坦钠的体外抗菌作用[J].华西药学杂志, 2009, 24(1):38
CHEN SW, ZHANG SC, WANG XJ, et al. In vitro antibacterial activities of different ratios from matching cefotaxime/ tazobactam [J].West Chin J Pharm Sic, 2009, 24(1):38
[3] 孙淑芬, 董伟林. 高效液相色谱法测定血液中头孢噻肟钠的浓度[J].中国药学杂志, 2001, 10(36):697
SUN SF, DONG WL. Determination of cefotaxime sodium in serum by HPLC [J].Chin Pharm J, 2001, 10(36):697
[4] 李进, 张培培, 姚尚辰, 等. 注射用哌拉西林钠他唑巴坦钠的聚合物杂质分析[J].药物分析杂志, 2019, 39(7):1279
LI J, ZHANG PP, YAO SC, et al. Analysis of polymer impurities in piperacillin sodium and tazobactam sodium for injection [J].Chin J Pharm Anal, 2019, 39(7):1279
[5] 郭阳, 孙德助, 宋敏, 等. 注射用头孢曲松钠-他唑巴坦钠人体药代动力学[J].中国药科大学学报, 2011, 42(4):354
GUO Y,SUN DZ,SONG M,et al. Pharmacokinetics of ceftriaxone sodium-tazobactam sodium for injection in healthy Chinese volunteers [J].J Chin Pharm Univ, 2011, 42(4):354
[6] 吕媛, 单爱莲, 孙路路, 等. 单剂量头孢他定/他唑巴坦钠(3∶1)在中国健康人体的药代动力学[J].中国临床药理学杂志, 2009, 25(2):123
LÜ Y, SHAN AL, SUN LL, et al. Pharmacokinetics of single-dose ceftazidime/tazobactam (3∶1) in healthy volunteers[J].Chin J Clin Pharm, 2009, 25(2):123
[7] 李方方, 顾世芬, 陈汇. 静脉滴注头孢哌酮/他唑巴坦复方制剂的健康人体药动学[J].中国药学杂志, 2007, 42(15):1181
LI FF, GU SF, CHEN H. Pharmacokinetics of cefoperazone/tazobactam in healthy volunteers after an intravenous administration [J].Chin Pharm J, 2007, 42(15):1181
[8] 孙亚欣, 肇丽梅, 何晓静, 等. HPLC同时测定哌拉西林/他唑巴坦在健康人血浆和尿中的浓度[J].中国药学杂志, 2008, 43(2):1651
SUN YX, ZHAO LM, HE XJ, et al. Determination of piperacillin/tazobactam in human plasma and urine by high-performance liquid chromatography [J].Chin Pharm J, 2008, 43(2):1651
[9] MORTENSEN JS, JENSEN BP,ZHANG M, et al. Preanalytical stability of piperacillin, tazobactam, meropenem, and ceftazidime in plasma and whole blood using liquid chromatography-tandem mass spectrometry[J].Ther Drug Monit, 2019, 41(4):538
[10] 冯金泉, 吴华, 冯文利, 等. HPLC-MS/MS法同时测定人血浆和尿液中哌拉西林他唑巴坦的浓度[J].中国药物应用与监测, 2010, 7(3):144
FENG JQ, WU H, FENG WL, et al. Simultaneous determination of piperacillin and tazobactam in human plasma and urine by HPLC-MS/MS[J].Chin J Drug Appl Monitor, 2010, 7(3):144
[11] 张娟, 陈笑艳, 戴晓健, 等. 正负离子切换液相色谱串联质谱法同时测定人血浆中头孢他啶和他唑巴坦[J].药物分析杂志, 2012, 32(1):83
ZHANG J, CHEN XY,DAI XJ, et al. Simultaneous determination of ceftazidime and tazobactam in human plasma with sequential positive and negative ionization liquid chromatography-tandem mass spectrometric detection [J].Chin J Pharm Anal, 2012, 32(1):83
[12] 孙路路, 单爱莲, 吕媛. 注射用头孢他啶/他唑巴坦(5∶1)在中国健康人体的多次给药的药代动力学[J].中国临床药理学杂志, 2013, 29(9):669
SUN LL, SHAN AL, LÜ Y. Pharmacokinetics of ceftazidime/tazobactam (5∶1) after multiple intravenous infusion administration in Chinese health volunteers [J].Chin J Clin Pharmacol, 2013, 29(9):669
[13] NEUGEBAUER S,WICHMANN C, SIBYLLE BS, et al. Simultaneous quantification of nine antimicrobials by LC-MS/MS for therapeutic drug monitoring in critically Ill Patients[J].Ther Drug Monit,2019, 41(1):29
[14] POPOWICZ ND,O′HALLORAN SJ,FITZGERALD D, et al. A rapid, LC-MS/MS assay for quantification of piperacillin and tazobactam in human plasma and pleural fluid; application to a clinical pharmacokinetic study[J].J Chromatogr Anal Technol Biomed Life Sci, 2018, 1081-1082:58
[15] 陈柠, 孙鲁宁, 胡文卉, 等. 液相色谱串联质谱法测定人尿液中头孢噻肟和他唑巴坦含量及在中国健康志愿者中的尿药排泄特征研究[J].药学与临床研究, 2020,28(1):6
CHEN N, SUN LN, HU WH, et al. Determination of cefotaxime and tazobactam in human urine by LC-MS/MS and study on their urinary excretion [J].Pharm Clin Res, 2020,28(1):6
