Abstract：
Changes to ivermectin (IVM [22,23-dihydro avermectin B1a + 22,23-dihydro avermectin B1b]) toxicokinetics (TK) with and without P-glycoprotein (P-gp) inhibition by cyclosporin A (CsA) were examined in rainbow trout (Oncorhynchus mykiss). Rainbow trout were injected with 175 μg/kg 3H-IVM (8.6 μCi/mg IVM) with or without co-administration of 480 μg/kg CsA into the caudal vasculature. Fish were sacrificed at various time points (0.25, 0.5, 1, 3, 24, 48, 96, and 168 h) for organ and tissue sampling (blood, liver, kidney, gill, intestines, brain [5 regions], eye, gonad, and fat) which were analyzed for IVM-derived radioactivity. The IVM concentration decreased over time in blood, liver, kidney, and gill, while concentrations in other tissues remained constant. The highest maximum IVM concentration (Cmax) was found in kidney, followed by liver; the lowest Cmax was found in eye, followed by brain and adipose tissue. The highest % of the administered dose was found in the blood 15 min post-IVM administration, followed by the intestine at 60 min post-IVM administration. P-gp inhibition by CsA did not significantly affect calculated TK parameters (AUC [7.33 ± 0.73 - 11.5 ± 2.5 mg•h/kg], mean residence time [84.7 ± 21 - 125 ± 55 h], T1/2 [58.7 ± 15 - 86.8 ± 38 h], clearance rate [0.0152 ± 0.0033 - 0.0239 ± 0.0024 L/kg•h], or volume of distribution [1.91 ± 0.47 - 2.02 ± 0.33 L/kg]), but resulted in small but significant changes in the % administered dose found in blood and medulla. These results suggest that P-gp plays a limited role in overall IVM TK, and that its role in xenobiotic protection may be much less robust in fish than it is in mammals.
摘要：
在虹鳟鱼（Oncorhynchusmykiss）中检查了有和没有环孢菌素A（CsA）抑制的伊维菌素（IVM[22,23-二氢阿维菌素B1a22,23-二氢阿维菌素B1b]）毒物动力学（TK）的变化。将虹鳟鱼注射175μg/kg3H-IVM（8.6μCi/mgIVM），并将或不将480μg/kgCsA共同施用到尾脉管系统中。在不同时间点（0.25、0.5、1、3、24、48、96和168小时）处死鱼，以进行器官和组织采样（血液，肝脏,肾,吉尔,肠子,大脑[5个区域]，眼睛,性腺,和脂肪）进行了IVM衍生的放射性分析。血液中的IVM浓度随着时间的推移而下降，肝脏,肾,还有gill,而其他组织中的浓度保持恒定。在肾脏中发现了最高的最大IVM浓度（Cmax），其次是肝脏；最低的Cmax在眼睛中发现，其次是大脑和脂肪组织。在IVM给药后15分钟的血液中发现了最高的给药剂量百分比。随后在IVM施用后60分钟进行肠。CsA对P-gp的抑制作用对计算的TK参数没有显着影响（AUC[7.33±0.73-11.5±2.5mg•h/kg]，平均停留时间[84.7±21-125±55小时]，T1/2[58.7±15-86.8±38小时]，清除率[0.0152±0.0033-0.0239±0.0024L/kg•h],或分布体积[1.91±0.47-2.02±0.33L/kg]），但导致血液和髓质中%给药剂量的微小但显著的变化。这些结果表明，P-gp在整体IVMTK中起着有限的作用，而且它在异种生物保护中的作用在鱼类中可能比在哺乳动物中弱得多。
