Department of Pharmacy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China.
Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei Province, 050000, China.
Toxicol Lett. 2021 Mar 1;338:78-84. doi: 10.1016/j.toxlet.2020.12.004. Epub 2020 Dec 9.
Amphotericin B (AmB), an effective polyene drug with broad spectrum antifungal activity, is used for serious fungal infections. Liposomal amphotericin B (LAmB) is a lipid dosage form, which has a significantly improved toxicity profile compared with conventional amphotericin B deoxycholate (DAmB). This study focused on verifying the gender differences in the acute toxicity of LAmB and further exploring its causes. Acute toxicity study of LAmB and DAmB were performed in rats, and toxicity responses and mortality of different sexes were observed and recorded. Concentrations of AmB in rat plasma and tissues were determined by a fully validated UPLC-MS/MS assay. The results demonstrated that LAmB showed significant gender differences in acute toxicity, with more severe toxic symptoms and higher mortality for female rats at different doses, but the same differences were not observed for DAmB under the same condition. To explore the cause of differences, toxicokinetic and tissue distribution studies were performed and the results showed that female animals had higher drug exposure, longer half-life and lower plasma clearance compared to male rats, and the drug was mostly distributed in the liver and kidneys, in which female rats displayed a significant higher concentration than that of male rats.
两性霉素 B（AmB）是一种具有广谱抗真菌活性的有效多烯类药物，用于治疗严重的真菌感染。脂质体两性霉素 B（LAmB）是一种脂质剂型，与传统两性霉素 B 去氧胆酸盐（DAmB）相比，其毒性谱显著改善。本研究旨在验证 LAmB 急性毒性的性别差异，并进一步探讨其原因。在大鼠中进行了 LAmB 和 DAmB 的急性毒性研究，观察并记录了不同性别大鼠的毒性反应和死亡率。采用完全验证的 UPLC-MS/MS 测定法测定大鼠血浆和组织中的 AmB 浓度。结果表明，LAmB 在急性毒性方面表现出显著的性别差异，不同剂量下雌性大鼠的毒性症状更严重，死亡率更高，但在相同条件下，DAmB 没有观察到相同的差异。为了探讨差异的原因，进行了毒代动力学和组织分布研究，结果表明，与雄性大鼠相比，雌性动物的药物暴露量更高，半衰期更长，血浆清除率更低，药物主要分布在肝脏和肾脏中，其中雌性大鼠的浓度明显高于雄性大鼠。
