基于微透析技术的连续性肾脏替代治疗脓毒症兔模型美罗培南药代动力学/药效学研究  

Pharmacokinetics/pharmacodynamics(PK/PD)of meropenem during continuous renal replacement therapy in a septic rabbits model based on microdialysis technology

作　　者：邵莹 王丹 SHAO Ying;WANG Dan(Drug Clinical Trial Institution,Hebei Yanda Hospital,Langfang 065201,China;Department of Orthopedics,PLA Rocket Force Characteristic Medical Center,Beijing 100000,China)

机构地区：[1]河北燕达医院药物临床试验机构,河北廊坊065201 [2]中国人民解放军火箭军特色医学中心,北京100000

出　　处：《中国药理学与毒理学杂志》2025年第3期199-207,共9页Chinese Journal of Pharmacology and Toxicology

基　　金：河北省省级科技计划项目(22377725D)。

摘　　要：目的 研究美罗培南在兔血浆、肺、肌肉和皮肤组织药代动力学/药效学(PK/PD),探讨脓毒症和连续性肾脏替代治疗(CRRT)对美罗培南PK/PD靶值达标率(PTA)的影响。方法 24只新西兰大白兔随机分为4组,分别为脓毒症行CRRT组、脓毒症组、正常行CRRT组和正常对照组,采用盲肠结扎穿刺法建立脓毒症模型,造模成功后6h,模拟人体给药剂量1 g,换算为兔的给药剂量[(1 000/60)×3.27]为54.5 mg·kg~(-1),各组通过自动输液泵静脉输液给药0.5 h,行CRRT组在开始给药的同时行CRRT治疗,采用微透析技术分别收集各组4部位0~480 min的微透析样本,每隔30 min收集1次,采用液相色谱-串联质谱(LC-MS/MS)测定美罗培南浓度,绘制浓度-时间曲线,计算曲线下面积(AUC)、达峰时间(T_(max))、半衰期(t_(1/2))和最大药物浓度(C_(max))等。应用蒙特卡洛模拟(MCS)结合最低抑菌浓度(MIC)和PK参数分析美罗培南在不同组织的PTA。以给药间隔内游离药物浓度[f]超过4倍MIC的时间百分比>40%(%fT>4MIC>40%)和C_(max)/MIC值>4为药效学目标进行研究。结果与正常对照组比较,脓毒症组皮肤组织各项PK参数无显著性变化,其他组织C_(max)均显著减低。与脓毒症组比较,脓毒症行CRRT组血浆和皮肤组织浓度-时间曲线AUC显著升高,肺和肌肉组织AUC显著降低(P<0.01)。以%fT>4MIC>40%为目标值,MIC=1 mg·L^(-1)时,脓毒症行CRRT组血浆和皮肤,正常行CRRT组肌肉,以及正常对照组肺、肌肉和皮肤组织,PTA>90%;MIC=2 mg·L^(-1)时,脓毒症行CRRT组皮肤和正常对照组肺组织,PTA>90%;MIC=4 mg·L^(-1)时,所有组织PTA均<90%。MIC为1、2或4 mg·L^(-1),所有组织C_(max)/MIC>4的概率均>90%。正常对照组各组织PTA与C_(max)和AUC大小无关联;除MIC=4 mg·L^(-1)时皮肤组织,脓毒症组各组织PTA均随C_(max)降低而降低;脓毒症行CRRT组血浆和皮肤组织PTA随AUC升高而升高,肌肉组织PTA随AUC降低而降低,肺组织除MIC=1 mg·L^(-1),PTA均�OBJECTIVE To study the pharmacokinetics/pharmacodynamics(PK/PD)profiles of meropenem in the plasma,lung,muscle and skin tissues of rabbits,and to explore the effects of sepsis and continuous renal replacement therapy(CRRT)on the probability of target attainment(PTA)of meropenem.METHODS Twenty-four New Zealand rabbits were randomly divided into four equal groups:sepsis-CRRT group,sepsis group,normal-CRRT group and normal control group.Six hours after a rabbit model of sepsis was established via cecal ligation and puncture(CLP)surgery,an auto-matic infusion pump with meropenem[(1000/60)×3.27=54.5 mg·kg^(-1),converted from that of humans(1g)to that of rabbits]was used to administer the drug to the animals for 0.5 h,while CRRT was started simultaneously with drug administration in the CRRT group.Microdialysis samples were collected from 4 target sites of each group once every 30 min for 480 min.The concentration of meropenem was deter-mined using liquid chromatography-tandem mass spectrometry(LC-MS/MS)before a concentration-time curve was constructed.Pharmacokinetic parameters such as the peak concentration(C_(max)),time to reach peak concentration(Tmax),area under the concentration-time curve(AUC),and elimination half-life(t1/2)were calculated using a non-atrioventricular model.Monte Carlo simulation(MCS)was performed at various minimum inhibitory concentrations(MICs)using pharmacokinetic parameters of meropenem to assess the probability of target attainment(PTA).The predefined PK/PD target was%fT>4MIC>40%,where the percentage of time that the free drug concentration[f]exceeded 4 times that of the MIC during a dosing interval was above 40%and C_(max)/MIC exceeded 4.RESULTS The results indicated no statistically significant differences between the PK parameters of skin tissue in the normal control group and sepsis group,whereas C_(max) of other tissues was significantly lower in the sepsis group than in the normal control group(P<0.01).AUCplasma and AUCskin were significantly increased(P<0.01),while AUClung and AUC

关 键 词：美罗培南 脓毒症 微透析 药代动力学/药效学 蒙特卡洛模拟 

分 类 号：R969[医药卫生—药理学]