己烯雌酚及代谢物在鲫鱼体内的组织分布及药物代谢动力学

Tissue Distribution and Pharmacokinetics of Diethylstilbestrol and Its Metabolite Dienestrol in Carassius auratus

为全面了解己烯雌酚在鲫鱼体内的残留、消除和药物动力学特征,采用超高效液相色谱-串联质谱法,研究口服灌药给药时己烯雌酚及其主要代谢物双烯雌酚在鲫鱼体内的组织分布和药物代谢动力学。在水温(12±2)℃条件下,鲫鱼口服灌药0.1,1.0 mg/(kg bw)和10.0 mg/(kg bw)后,其血浆、肌肉和肝脏中己烯雌酚浓度-时间曲线关系符合一级吸收的二室开放动力学模型。以剂量1.0 mg/(kg bw)为例,3种组织中己烯雌酚峰值水平肝脏最高,肌肉次之,血浆最低,己烯雌酚的平均消除速率均较快,分别为26.7μg/(L·h),3.75μg/(kg·h)和9.26μg/(kg·h),在12,144 h和144 h各降至检出限以下。己烯雌酚代谢物———双烯雌酚在鲫鱼的血浆、肌肉和肝脏中药物水平的变化趋势与己烯雌酚基本相似,均表现先升高后降低的趋势。双烯雌酚分别在血浆、肌肉和肝脏中3,10 h和8 h达到最大浓度值,12,144 h和144 h降至检出限以下。采用DAS2.0药物代谢动力学参数计算程序,处理口服灌药后鲫鱼体内的己烯雌酚浓度-时间数据,计算有关药物代谢动力学参数。以1.0 mg/(kg bw)己烯雌酚为例,结果发现:血浆、肌肉、肝脏的AUC相差较大,说明不同组织对己烯雌酚的蓄积能力有差别;血浆、肌肉和肝脏的CL/F值依次为1.041,0.121 L/(h·kg)和0.052 L/(h·kg),说明己烯雌酚在鲫鱼体内分布广,消除较快。本试验中,在己烯雌酚0.1,1.0 mg/(kg bw)和10.0 mg/(kg bw)口服灌药浓度下,建议其消除期分别定为4,6 d和7 d。水温高时可适当缩短消除期,水温低时可适当延长消除期。本研究的药时曲线可为鲫鱼己烯雌酚的消除净化提供基础数据。

Tissue distribution and pharmacokinetics of Diethylstilbestrol and its metabolite Dienestrol in plasma,muscle and liver of Carassius auratus under laboratory conditions using single oral administration was studied by ultra performance liquid chromatogram tandem mass spectrometry in this work. After administration by single oral of 0.1, 1.0mg/（kg bw） and 10.0 mg/（kg bw）, Diethylstilbestrol concentrations in plasma, muscle and liver versus time were well described by a two-department open model with first-order absorption. For example, after single oral of 1.0 mg/（kg bw）,the biggest concentration of Diethylstilbestrol in liver was highest, the next was muscle and the lowest was plasma. The average elimination speed was 26.7 μg/（L·h）, 3.75 μg/（kg·h） and 9.26 μg/（kg·h） of plasma, muscle and liver, showing that Diethylstilbestrol could eliminate fast in Carassius auratus. Diethylstilbestrol was no detected after oral administration of 12 h, 144 h and 144 h. The variation of Dienestrol concentrations in plasma, muscle and liver of Carassius auratus was similar with Diethylstilbestrol, first increased and then decreased. Concentrations of Dienestrol in plasma, muscle and liver could reach peak after oral administration of 3, 10 h and 8 h, and no detected after 12, 144 h and 144 h. DAS2.0 pharmacokinetic parameter calculation program was used to process Diethylstilbestrol content-time datas and to calculate the relevant pharmacokinetic parameters of Diethylstilbestrol. For example, in the concentration of 1.0 mg/（kg bw）,the results indicated that area under concentration-time curve（AUC） differed greatly in plasma, muscle and liver of Carassius auratus and the tissues had different accumulation capability. The overall clearance rate of Diethylstilbestrol in plasma, muscle and liver was 1.041, 0.121 L/（h·kg） and 0.052 L/（h·kg）, indicating distribution was dispersed and elimination was fast. Under the experimental conditions, when Carassius auratus using single oral administration of0.1, 1.0 mg/（kg bw） and 10.0 mg/（kg bw）, it was recommended withdrawal period of 4, 6 d and 7 d respectively. When the water temperature was highter than the experimental conditions, the withdrawal period could be shorten; and extended in lower water temperature. The concentrations versus time curves of Diethylstilbestrol in Carassius auratus provided useful information for studying decontamination of Carassius auratus that had Diethylstilbestrol contamination.