Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia, Canada.
Vet Res Commun. 2024 Oct;48(5):3139-3155. doi: 10.1007/s11259-024-10480-3. Epub 2024 Aug 6.
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 H-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 (C) was found in kidney, followed by liver; the lowest C 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 mgh/kg], mean residence time [84.7 ± 21 - 125 ± 55 h], T [58.7 ± 15 - 86.8 ± 38 h], clearance rate [0.0152 ± 0.0033 - 0.0239 ± 0.0024 L/kgh], 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.
研究了伊维菌素（IVM[22,23-二氢阿维菌素 B1a+22,23-二氢阿维菌素 B1b]）在有和没有环孢菌素 A（CsA）对 P-糖蛋白（P-gp）抑制时的毒代动力学（TK）变化，在虹鳟鱼（Oncorhynchus mykiss）中进行了研究。虹鳟鱼尾静脉注射 175μg/kg H-IVM（8.6μCi/mg IVM），同时或不合并腹腔内注射 480μg/kg CsA。在 0.25、0.5、1、3、24、48、96 和 168 小时时，对血液、肝脏、肾脏、鳃、肠道、脑（5 个区域）、眼睛、性腺和脂肪等器官和组织进行取样，分析 IVM 衍生放射性。IVM 浓度在血液、肝脏、肾脏和鳃中随时间下降，而在其他组织中保持不变。肾脏中的最大 IVM 浓度（C）最高，其次是肝脏；眼睛中的 C 最低，其次是脑和脂肪组织。IVM 给药后 15 分钟血液中发现的最大给药剂量百分比最高，60 分钟后肠道中发现的给药剂量百分比最高。CsA 对 P-gp 的抑制作用并未显著影响计算的 TK 参数（AUC[7.33±0.73-11.5±2.5mgh/kg]、平均驻留时间[84.7±21-125±55h]、T[58.7±15-86.8±38h]、清除率[0.0152±0.0033-0.0239±0.0024L/kgh]或分布容积[1.91±0.47-2.02±0.33L/kg]），但导致血液和髓质中发现的给药剂量百分比发生微小但显著的变化。这些结果表明，P-gp 在 IVM 的整体 TK 中发挥的作用有限，其在鱼类中的外来生物保护作用可能远不如哺乳动物中的作用强大。
