Gender differences in acute toxicity, toxicokinetic and tissue distribution of amphotericin B liposomes in rats

• Published in: Toxicology letters Vol. 338; pp. 78 - 84
• Main Authors: Wang, Dong, Zhang, Wei, Ju, Jie-Xi, Wang, Lu-Jia, Huang, Ru-Yu, Xu, Yan-Fang, Zhang, Hai-Lin, Qi, Jin-Long
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2021
• Subjects: Acute toxicity; Amphotericin B - administration & dosage; Amphotericin B - pharmacokinetics; Amphotericin B - toxicity; Amphotericin B liposome; Animals; Antifungal Agents - administration & dosage; Antifungal Agents - pharmacokinetics; Antifungal Agents - toxicity; Chromatography, High Pressure Liquid; Female; Gender differences; Kidney - metabolism; Liver - metabolism; Male; Rats; Rats, Sprague-Dawley; Sex Factors; Tandem Mass Spectrometry; Tissue Distribution; Toxicity Tests, Acute; Toxicokinetic; Toxicokinetics; UPLC-MS/MS; UPLC-MS/MS; Gender differences; Tissue distribution; Amphotericin B liposome; Toxicokinetic; Acute toxicity
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2020.12.004

[Display omitted] •The gender differences in toxicity of amphotericin B liposomes (LAmB) in rat were reported for the first time, and mechanism underlying were revealed.•A sensitive and rapid UPLC–MS/MS approach was developed and the validation process was fully performed for the determination of amphotericin B (AmB) in rat plasma and various tissues.•This study can contribute to drug development and safer use of LAmB clinically. 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.