Cothrell Andrew, Orugunty Ravi S, Smith Leif
Department of Biology, Texas A&M University, College Station, Texas, USA.
Antimicrobial Division, Sano Chemicals Inc., Bryan, Texas, USA.
J Mass Spectrom. 2025 Apr;60(4):e5121. doi: 10.1002/jms.5121.
Fungal infections are caused by opportunistic pathogens that can be life threatening and have been growing in prevalence. Many clinically relevant pathogens have resistance to or are developing resistance to the commonly used antifungal treatments. Occidiofungin (OCF) is a unique cyclic lipoglycopeptide with a novel structure that includes noncanonical amino acid in its covalent structure. It exhibits broad spectrum antifungal activity and has activity against drug resistant Candida species. Occidiofungin is a fungicidal compound that has a novel mechanism of action in which it disrupts higher order actin structures. Currently, occidiofungin is being developed for use in treating vulvovaginal candidiasis (VVC) and recurrent vulvovaginal candidiasis (RVVC). This study describes the development and application of a bioanalytical method for the quantification of occidiofungin in rabbit plasma. Method development was performed to quantify occidiofungin in rabbit plasma after intravaginal administration of a hydrogel containing occidiofungin. The method was validated with a linear range of 30-15 000 ng/mL in rabbit plasma. Precision, accuracy, calibration curve linearity, and stability of drug in plasma were established in quality controls. Extract stability, matrix effects, and recovery of drug in the extract were also determined. This study supported a repeat dose toxicity study in rabbits to determine occidiofungin pharmacokinetics and toxicokinetics. The pharmacokinetic and toxicokinetic primarily showed plasma concentrations of occidiofungin below the limit of quantification (BLOQ), suggesting that OCF-B does not readily cross the vaginal epithelial membrane.
真菌感染由机会性病原体引起，这些病原体可能危及生命且发病率一直在上升。许多临床相关病原体对常用的抗真菌治疗产生了耐药性或正在产生耐药性。奥西地芬净（OCF）是一种独特的环状脂糖肽，具有新颖的结构，其共价结构中包含非经典氨基酸。它具有广谱抗真菌活性，对耐药念珠菌属也有活性。奥西地芬净是一种杀真菌化合物，具有破坏高阶肌动蛋白结构的新作用机制。目前，奥西地芬净正被开发用于治疗外阴阴道念珠菌病（VVC）和复发性外阴阴道念珠菌病（RVVC）。本研究描述了一种生物分析方法的开发和应用，用于定量兔血浆中的奥西地芬净。进行方法开发以定量经阴道给予含奥西地芬净水凝胶后兔血浆中的奥西地芬净。该方法在兔血浆中的线性范围为30 - 15000 ng/mL，经验证有效。在质量控制中确定了精密度、准确度、校准曲线线性以及药物在血浆中的稳定性。还测定了提取物稳定性、基质效应和提取物中药物的回收率。本研究支持在兔中进行重复剂量毒性研究，以确定奥西地芬净的药代动力学和毒代动力学。药代动力学和毒代动力学主要显示奥西地芬净的血浆浓度低于定量限（BLOQ），这表明OCF - B不易穿过阴道上皮膜。
