Data_Sheet_1_Pharmacokinetics and Tissue Residue Profiles of Enrofloxacin in Crucian Carp (Carassius auratus gibelio) Following Single and Multiple Oral Administration.XLSX

The pharmacokinetics, tissue distribution, and elimination of enrofloxacin (ENR) and its metabolite ciprofloxacin (CIP) were investigated to the crucian carp (Carassius auratus gibelio) after single (20 mg/kg b. w.) and multiple oral administration (20 mg/kg b.w. one time daily for 5 days) at 28°C. The concentrations of ENR and CIP in the plasma and tested tissues (muscle/skin, liver, and kidney) were detected simultaneously by high-performance liquid chromatography (HPLC), and the pharmacokinetic data were analyzed with a non-compartmental model using WinNonLin 6.1 PK software (Pharsight Corporation, Mountain View, CA, USA). The pharmacokinetic characteristics of ENR in crucian carp exhibited slow absorption, wide tissue distribution, and long elimination half-life. In the single-dose group, the peak concentrations (Cmax) of ENR in the plasma, muscle/skin, liver, and kidney were 8.93 μg/mL, 13.9 μg/g, 31.2 μg/g, and 27.3 μg/g, respectively, observed at 3 h, 6 h, 1 h, and 3 h after dosing. The elimination half-lives (T1/2λz) of ENR in plasma, muscle/skin, liver, and kidney were calculated to be 67.4, 82.8, 94.4, and 114 h, respectively. In the multiple-dose group, the Cmax of ENR in the plasma, muscle/skin, liver, and kidney were 18.4 μg/mL, 26.8 μg/g, 82.8 μg/g, and 74.5 μg/g, respectively, achieved at 3 h, 6 h, 1 h, and 1 h after the last dose. The T1/2λz of ENR in the plasma, muscle/skin, liver, and kidney were calculated to be 76.4 h, 91.5 h, 114 h, and 148 h, respectively. During the multiple-dose administration, significant accumulations of ENR and CIP were observed in the plasma and tissues of crucian carp, possibly due to their long elimination half-lives. In both dose groups, the AUC0−∞ for both ENR and CIP followed the order of liver > kidney > muscle/skin > plasma. The finding suggested that the liver may play an important role in the metabolism of ENR. According to the calculated PK/PD indices of Cmax/minimum inhibitory concentrations (MIC) and AUC24h/MIC, the multiple-dose regimen would be highly effective against pathogenic bacteria with a MIC value of ≤ 1.84 μg/ml. Depletion studies indicated that a withdrawal period of at least 29 or 32 days was necessary to guarantee food security after single or multiple oral gavage administration at 28°C.

本研究以28℃条件下的异育银鲫（Carassius auratus gibelio）为受试对象，探究单次（20 mg/kg体质量）与多次（每日1次，20 mg/kg体质量，连续给药5 d）口服给药后，恩诺沙星（enrofloxacin，ENR）及其代谢物环丙沙星（ciprofloxacin，CIP）在鱼体内的药代动力学、组织分布与消除规律。
采用高效液相色谱法（high-performance liquid chromatography，HPLC）同时检测血浆及待测组织（肌肉/皮肤、肝脏、肾脏）中ENR与CIP的浓度；使用WinNonLin 6.1药代动力学软件（美国加利福尼亚州山景城Pharsight公司开发）采用非房室模型对药代动力学数据进行分析。
恩诺沙星在异育银鲫体内的药代动力学特征表现为吸收缓慢、组织分布广泛、消除半衰期较长。单次给药组中，血浆、肌肉/皮肤、肝脏、肾脏中ENR的峰浓度（Cmax）分别为8.93 μg/mL、13.9 μg/g、31.2 μg/g与27.3 μg/g，达峰时间分别为给药后3 h、6 h、1 h与3 h；其在各组织与血浆中的消除相半衰期（T1/2λz）分别为67.4 h、82.8 h、94.4 h与114 h。
多次给药组中，血浆、肌肉/皮肤、肝脏、肾脏中ENR的峰浓度分别为18.4 μg/mL、26.8 μg/g、82.8 μg/g与74.5 μg/g，末次给药后达峰时间分别为3 h、6 h、1 h与1 h；其在各组织与血浆中的消除相半衰期分别为76.4 h、91.5 h、114 h与148 h。
多次给药期间，恩诺沙星与环丙沙星在异育银鲫血浆及各组织中出现明显蓄积，这可能与其较长的消除半衰期有关。
两个给药组中，ENR与CIP的零时至无穷大曲线下面积（AUC0−∞）均遵循肝脏＞肾脏＞肌肉/皮肤＞血浆的顺序，提示肝脏可能在恩诺沙星的代谢过程中发挥重要作用。
根据峰浓度（Cmax）/最低抑菌浓度（minimum inhibitory concentrations，MIC）与24小时曲线下面积（AUC24h）/MIC计算得到的药代动力学/药效学（PK/PD）指数，该多次给药方案对最低抑菌浓度≤1.84 μg/mL的致病菌具有良好的抗菌效果。
消除试验结果表明，在28℃条件下单次或多次口服灌胃给药后，需至少29 d或32 d的休药期方可保障食用安全性。