Akyol Busra Aslan, Gokbulut Cengiz
Department of Veterinary Pharmacology and Toxicology, Institute of Health Sciences, Balikesir University, CoHE 100/2000 Scholarship Holder, University Rectorate Çağış Campus 17. Km, Bigadiç Caddesi, 10145, Balikesir, Turkey.
Department of Medical Pharmacology, Faculty of Medicine, Balikesir University, University Rectorate Çağış Campus 17. Km, Bigadiç Caddesi, 10145, Balikesir, Turkey.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Mar;397(3):1841-1852. doi: 10.1007/s00210-023-02738-5. Epub 2023 Sep 28.
Intravenous lipid emulsion (ILE) has been widely used as an effective antidote in both veterinary and human medicine for the treatment of acute intoxications caused by drugs and pesticides with high lipid solubility. This study was conducted to investigate the effect of ILE co-administration on the kinetic dispositions of ivermectin (IVM) and carprofen (CRP) following intravenous bolus administration at subtoxic doses in rabbits.Twenty-four male New Zealand rabbits weighing 2.78 ± 0.2 kg were used in this study. Rabbits were divided into four groups (Group 1: IVM and Group 2: IVM + ILE or Group 3: CRP and Group 4: CRP + ILE), each group consisting of 6 animals. In the IVM study, Group 1 received IVM (0.6 mg/kg) alone while Group 2 received IVM (0.6 mg/kg) and ILE (2.5 ml/kg). In the CRP study, Group 3 received CRP (12 mg/kg) alone while Group 4 received CRP (12 mg/kg) and ILE (2.5 ml/kg). In both drug groups, ILE was administered 3 times as an i.v. bolus at the 10th min and repeated 4th and 8th h after the drug administration. Blood samples were collected from the auricular vein at various times after drug administration. The drug concentrations in plasma samples were determined by high-pressure liquid chromatography. Kinetic parameters were calculated using a non-compartmental model for both CRP and IVM.The C and area under the concentration-time curve from zero up to ∞ (AUC) values were significantly greater with ILE co-administration (2136 ng/ml and 360.84 ng.d/ml) compared to the IVM alone (1340.63 ng/ml and 206 ng.d/ml), respectively. Moreover, the volume of distribution (Vd) and clearance (Cl) of IVM were reduced by approximately 42% and 46% with ILE co-administration compared to IVM alone resulting in a reduction of the distribution and slower elimination, respectively. Similar differences in C, and Vd values were also observed in CRP with ILE co-administration compared to CRP alone. ILE co-administration changed significantly the kinetic profile of both IVM and CRP in rabbits, supporting the lipid sink theory in which highly lipid-soluble compounds are absorbed into the lipid phase of plasma from peripheral organs such as the heart and brain affected by the acute toxicity of the compounds.
静脉注射脂质乳剂（ILE）已在兽医学和人类医学中广泛用作一种有效的解毒剂，用于治疗由具有高脂溶性的药物和农药引起的急性中毒。本研究旨在调查在兔亚中毒剂量静脉推注给药后，ILE联合给药对伊维菌素（IVM）和卡洛芬（CRP）动力学处置的影响。本研究使用了24只体重为2.78±0.2千克的雄性新西兰兔。将兔分为四组（第1组：IVM组；第2组：IVM+ILE组；第3组：CRP组；第4组：CRP+ILE组），每组6只动物。在IVM研究中，第1组单独接受IVM（0.6毫克/千克），而第2组接受IVM（0.6毫克/千克）和ILE（2.5毫升/千克）。在CRP研究中，第3组单独接受CRP（12毫克/千克），而第4组接受CRP（12毫克/千克）和ILE（2.5毫升/千克）。在两个药物组中，ILE均在第10分钟静脉推注给药3次，并在给药后第4小时和第8小时重复给药。给药后在不同时间从耳静脉采集血样。通过高压液相色谱法测定血浆样品中的药物浓度。使用非房室模型计算CRP和IVM的动力学参数。与单独使用IVM相比，联合使用ILE时，IVM的血药浓度（C）和从零到无穷大的浓度-时间曲线下面积（AUC）值显著更高（分别为2136纳克/毫升和360.84纳克·天/毫升），而单独使用IVM时分别为1340.63纳克/毫升和206纳克·天/毫升。此外，与单独使用IVM相比，联合使用ILE时IVM 的分布容积（Vd）和清除率（Cl）分别降低了约42%和46%，导致分布减少和消除减慢。与单独使用CRP相比，联合使用ILE时CRP的C和Vd值也观察到类似差异。联合使用ILE显著改变了兔体内IVM和CRP的动力学特征，支持脂质池理论，即高脂溶性化合物从受化合物急性毒性影响的外周器官（如心脏和大脑）吸收到血浆的脂质相中。
