基于药代与药效动力学联合参数制定磺胺嘧啶在异育银鲫中的用药方案的研究

摘要

The aim of this research was to investigate dosing guideline of sulfadiazine in the prevention of pathogenic Aeromonashy-drophila(CAAh01) infection in crucian carp (Carassiusauratus). In this study, invitropharmacodynamic experiments of sulfadiazine against Aeromonashydrophila, combined with invivopharmacokinetic parameters post oral administration with different doses, were employed to determine reasonable medication regimen. The invitropharmacodynamic meters of sulfadiazine were determined to be:the minimum inhibitory concentration (MIC), 4-8μg/ml;the minimal bactericidal concentration (MBC), 24μg/ml;mutant prevention concentration (MPC), 72μg/ml;mutant selection window (MSW) of sulfadiazine on CAAh01, 4-72μg/ml. The invivotime-curves of drug concentrations on single administration demonstrated that the time of sulfadiazine concentration above MPC was 0 h at dos-age of 100 mg/kg;5 h at 200 mg/kg and 11 h at 300 mg/kg and 24 h at 400 mg/kg, respectively;in serum, the AUC0→24/MIC were 173.8635, 290. 5975, 415. 15 and 554. 99 at dosage of 100 mg/kg, 200 mg/kg, 300 mg/kg and 400 mg/kg, respectively;Cmax/MIC were 13. 16, 20. 164, 27. 456 and 29. 394 at the dosage of 100 mg/kg, 200 mg/kg, 300mg/kg and 400 mg/kg, respectively. Integrated parame-ters drawn from this study, including plasma concentration time maintained above the MPC , AUC0→24/MIC≥100 and Cmax/MIC>8, recommended daily oral dose of 400 mg/kg toward efficient therapy and prevention of selection of drug resistance, the withdrawal pe-riod should not be less than 31 days.%为研究磺胺嘧啶在异育银鲫嗜水气单胞菌性疾病治疗中的有效使用浓度,制定磺胺嘧啶对异育银鲫的精确用药方案,达到合理应用抗菌药物的目的,通过磺胺嘧啶针对嗜水气单胞菌CAAh01体外药效学实验,结合口灌不同剂量下的体内药动学参数,确定了不同剂量下磺胺嘧啶的理论给药方案。体外药效学试验研究结果显示,磺胺嘧啶对致病菌CAAh01的最小抑菌浓度（MIC）为4~8mg/mL,最小杀菌浓度（MBC）为24mg/mL,防耐药突变浓度（MPC）为72mg/m：,防耐药突变选择窗（MSW）为4~72mg/mL；系统比较不同浓度磺胺嘧啶在鲫体内的药时曲线,发现单次口灌100 mg/kg、200 mg/kg、300 mg/kg和400 mg/kg磺胺嘧啶时,维持血药浓度＞MPC的时间分别是0 h、5 h、11 h和23 h；核心PK-PD结合参数AUC0→24/MIC,分别是173.86、290.60、415.15和554.99；Cmax/MIC分别是13.16、20.16、27.46和29.39。综合血药浓度维持＞MPC时间, AUC0→24/MIC≥100、Cmax/MIC＞8的标准值,确定磺胺嘧啶用于鲫鱼细菌系疾病防治用药方案为：每日1次给药最大剂量为400 mg/kg,以100μg/kg为最高残留量计算,根据药代动力学曲线方程推断休药期不得低于31 d；实验研究结果可以鱼类的用药剂量作为人类临床用药剂量的理论指导与用药依据。