【作者】 刘文芳；

【导师】 程泽能；

【作者基本信息】 中南大学 ， 药剂学， 2009， 硕士

【摘要】 一、目的在健康志愿者中研究单次及多次静脉滴注给予注射用头孢噻肟钠他唑巴坦钠(6：1)后的药物动力学特征,以及他唑巴坦钠(TAZ)对头孢噻肟钠(CTX)药动学特征的影响。结合人体耐受性试验研究结果及临床前药理、毒理研究资料,为该药的Ⅱ期临床给药方案提供参考依据。二、方法1.单次给药药动学试验12名健康志愿者分为6组,每组男女各1人。按照给药方案(二重3×3拉丁方交叉试验设计)在三个周期内分别接受不同的剂量,周期问洗脱时间为3天。每周期给药后于不同的时间点采集肘静脉血约4mL。HPLC-UV法测定血浆中头孢噻肟钠及他唑巴坦钠的浓度,用DAS2.0软件计算药动学参数,并用SPSS11.0软件对参数进行统计分析。2.连续多次给药药动学试验9名健康志愿者(5名男性、4名女性)每天给药2次,每次给药2.0g,连续给药5天,在最后一次给药后于不同的时间点采集肘静脉血约4mL。HPLC-UV法测定血浆中头孢噻肟钠及他唑巴坦钠的浓度,DAS2.0软件计算药动学参数,并用SPSS11.0软件对参数进行统计分析。3.他唑巴坦钠对头孢噻肟钠药动学特征的影响研究12名健康志愿者随机分为两组,每组男女各3人。按照给药方案(2×2交叉试验设计)在两个周期内分别接受复方制剂(注射用头孢噻肟钠他哗巴坦钠(6：1))和单方制剂(注射用头孢噻肟钠),每天给药2次,每次给药2.0g,连续给药5天。周期问洗脱时间为3天。在每周期最后一次给药后于不同时间点采集肘静脉血约4mL。HPLC-UV法测定血浆中头孢噻肟钠的浓度, DAS2.0软件计算药动学参数,并用SPSS11.0软件对参数进行统计分析。三、结果1.单次给药药动学研究1.0g、2.0g、3.0g剂量组的头孢噻肟钠t1／2β分别为0.9±0.2、0.8±0.2、1.4±0.2h；AUC0-t分别为49.6±12.4、91.4±33.8、146.1±41.1 mg·h·L-1：AUC0-∞分别为53.6±13.0、97.8±34.6、156.1±41.7 mg·h·L-1：Cmax分别为37.2±7.7、90.7±20.6、99.3±23.6 mg·L-1；CL分别为18.7±3.8、20.6±4.4、19.4±3.6 L·h-1；MRT为1.3±0.2、1.2±0.2、1.3±0.2 h。2.0g、3.0g剂量组的他唑巴坦钠t1／2分别为0.5±0.1、0.5±0.2 h；AUC0-t分别为8.6±1.6、13.4±3.9 mg·h·L-1；AUC0-∞分别为9.8±1.8、14.6±4.1 mg·h·L-1；Cmax。分别为6.6±1.2、10.9±2.5 mg·L-1；CL分别为34.4±7.1、34.3±9.2 L·h-1；MRT分别为1.4±0.2、1.2±0.4 h。2.连续多次给药药动学研究头孢噻肟钠t1/2β为0.8±0.2 h；AUC0_t为92.5±26.3 mg·h·L-1；AUC0-∞为93.8±26.7 mg·h·L-1；Cmax为82.8±12.4 mg·L-1；CL为21.4±3.7 L·h-1；MRT为1.2±0.2 h。他唑巴坦钠t1/2为0.7±0.2 h；AUC0-∞为10.7±1.8 mg·h·L-1；AUC0-∞为11.5±1.9mg·h·L-1；Cmax为10.0±1.6 mg·L-1；CL为29.4±5.6 L·h-1；MRT为1.7±0.5 h。采集的谷浓度血样中均未检测出头孢噻肟钠及他唑巴坦钠。3.他唑巴坦钠对头孢噻肟钠药动学特征的影响研究复方制剂组与单方制剂组的头孢噻肟钠t1／2。分别为1.1±0.5、0.9±0.5 h；AUC0-t分别为139.3±17.6、129.1±18.2 mg·h·L-1；AUC0-∞分别为153.1±19.9、142.6±21.6mg·h·L-1；Cmax分别为99.0±11.6、92.2±14.7 mg·L-1；CL分别为13.1±2.6、14.1±2.8 L·h-1；MRT分别为1.4±0.2、1.3±0.2 h。采集的谷浓度血样中均未检测出头孢噻肟钠。四、结论1.在1.0-3.0g范围内,头孢噻肟钠和他唑巴坦钠在人体内的消除符合一级速率过程。2.多次给药与单次给予相同剂量比较,头孢噻肟钠的主要药动学参数均没有变化：他唑巴坦钠的Cmax、CL有变化。3.合用他唑巴坦钠对头孢噻肟钠的药动学参数无影响。更多还原

【Abstract】 OBJECTIVESTo study the single-dose and multiple-dose pharmacokinetic of cefotaxime and tazobactam in Chinese healthy volunteers,and then to study the pharmacokinetic interaction with cefotaxime and tazobactam.METHODS1.Single-dose pharmacokineticA randomized,crossover, Latin square study with three phases and a washout period of 3 days was carried out.12 healthy volunteers(6 males and 6 females) was divided randomly into six groups,and each group has one male and one female. Everyone were be taken with cefotaxime sodium tazobactam sodium for injection(6:1) with different dose(1.0g/2.0g/3.0g) in different phase.Blood samples were collected at difference time from volunteers’ulnar vain.Plasma concentration of cefotaxime and tazobactam was determined by HPLC-UV. The data was fit by DAS 2.0 to calculate the pharmacokinetic parameters,then the pharmacokinetic parameters were been analysised by SPSS 11.0.2.Multiple-dose pharmacokinetic9 healthy volunteers(5 males and 4 females)were be taken with cefotaxime sodium tazobactam sodium for injection(6:1)twice daily in 5 days with a dose 2.0g. Blood samples were collected before the dosage in day 3/4/5 and were collected after the last dosage. Plasma concentration of cefotaxime and tazobactam was determined by HPLC-UV. The data was fit by DAS 2.0 to calculate the pharmacokinetic parameters,then the pharmacokinetic parameters were been analysised by SPSS 11.0. 3. The pharmacokinetic interaction with cefotaxime and tazobactamA randomized,crossover study with two phases and a washout period of 3 days was carried out.12 healthy volunteers(6 males and 6 females) was divided randomly into two groups,and each group has three male and three female.Everyone were be taken with cefotaxime sodium tazobactam sodium for injection(6:1)or cefotaxime sodium for injection (twice daily in 5 days with a dose 2.0g)in different phase.Blood samples were collected before the dosage in day 3/4/5 and were collected after the last dosage in each phase.Plasma concentration of cefotaxime and tazobactam was determined by HPLC-UV. The data was fit by DAS 2.0 to calculate the pharmacokinetic parameters,then the pharmacokinetic parameters were been analysised by SPSS 11.0.RESULTS1.The results of single-dose pharmacokineticIn the single-dose(1.0g/2.0g/3.0g) study, the main pharmacokinetic parameters of cefotaxime were as follows:t1/2βwere 0.9±0.2,0.8±0.2,1.4±0.2 h;AUC0-t were 49.6±12.4,91.4±33.8,146.1±41.1 mg·h·L-1,AUC0-∞were 53.6±13.0,97.8±34.6,156.1±41.7mg·h·L-1,Cmax were 37.2±7.7,90.7±20.6,99.3±23.6 mg·L-1,CL were 18.7±3.8,20.6±4.4,19.4±3.6 L·h-1,MRT were 1.3±0.2,1.2±0.2,1.3±0.2h。The main pharmacokinetic parameters of tazobactam with dose 2.0g and 3.0g were as follows:t1/2 were 0.5±0.1,0.5±0.2h,AUC0-t were 8.6±1.6,13.4±3.9 mg·h·L-1, AUC0-∞were 9.8±1.8,14.6±4.1 mg·h·L-1,Cmax were 6.6±1.2,10.9±2.5 mg·L-1,CL were 34.4±7.1,34.3±9.2L·h-1,MRT were 1.4±0.2,1.2±0.4h。2.The results of multiple-dose pharmacokineticThe main pharmacokinetic parameters of cefotaxime were as follows:t1/2βwas 0.8±0.2h,AUCo-t was 92.5±26.3 mg·h·L-1,AUC0-∞was 93.8±26.7 mg·h·L-1,Cmax was 82.8±12.4 mg·L-1,CL was 21.4±3.7 L·h-1,MRT was 1.2±0.2h。The main pharmacokinetic parameters of tazobactam were as follows:t1/2 was 0.7±0.2 h,AUCo-t was 10.7±1.8 mg·h·L-1,AUC0-∞was 11.5±1.9 mg·h·L-1,Cmax was 10.0±1.6 mg·L-1,CL was 29.4±5.6 L·h-1 MRT was 1.7±0.5 h。The blood samples which been collected before the dosage were ND.3.The results of the pharmacokinetic interaction with cefotaxime and tazobactamThe main pharmacokinetic parameters of cefotaxime (took with cefotaxime sodium tazobactam sodium for injection(6:1) or cefotaxime sodium for injection)were as follows:t1/2βwere 1.1±0.5,0.9±0.5 h, AUC0-t were 139.3±17.6,129.1±18.2 mg·h·L-1, AUC0-∞were 153.1±19.9,142.6±21.6 mg·h·L-1,Cmax were 99.0±11.6、92.2±14.7 mg·L-1,CL were 13.1±2.6,14.1±2.8L·h-1,MRT were 1.4±0.2,1.3±0.2 h。The blood samples which been collected before the dosage were ND.CONCLUSIONS1.In the single-dose range from 1.0g to 3.0g,the process of cefotaxime and tazobactam in people conformed to first order kinetics.2. In the multiple-dose study, the pharmacokinetic parameters of cefotaxime have no significant difference from the likewise single-dose;but the pharmacokinetic parameters(Cmax and CL)of tazobactam have significant difference from the likewise single-dose.3.There is no pharmacokinetic interaction with cefotaxime and tazobactam.更多还原