Sahasranaman S, Issar M, Tóth G, Horváth Gy, Hochhaus G
Department of Pharmaceutics, University of Florida, Gainesville, Florida 32610, USA.
Pharmazie. 2004 May;59(5):367-73.
Mometasone furoate (MF) is a synthetic glucocorticoid with anti-inflammatory activity, which is used for the treatment of topical skin disorders, allergic rhinitis and treatment of mild to moderate persistent asthma. The focus of this study is to examine the stability of MF in simulated lung fluid (SLF) and to clearly identify the structure of the degradation products of MF by MS and NMR analysis. Mometasone furoate degradation leads to the formation of two products, D1 and D2 with significant pH dependence. The half-lives for the conversion of MF to D1 and subsequent conversion of D1 to D2 at 37 degrees C in SLF were 1.3 and 4.8 h respectively. LC-MS and NMR analysis confirmed that D1 is 9,11-epoxide mometasone furoate while D2 represents a new chemical structure that shows cyclization within the C17-C21 region. The biological activity of these degradation products was assessed in rat lung glucocorticoid receptor binding studies. D1 showed 4 fold greater receptor affinity to glucocorticoid receptors compared to dexamethasone. However, the receptor affinity for D2 was a log order lower than that for dexamethasone. The instability of MF in SLF resulted in two degradation products, one of the degradation products showing glucocorticoid receptor activity, the other representing a new cyclized structure whose pharmacological properties have not been described. The biological significance of these degradation products is unknown.
糠酸莫米松（MF）是一种具有抗炎活性的合成糖皮质激素，用于治疗局部皮肤疾病、过敏性鼻炎以及轻度至中度持续性哮喘。本研究的重点是检测MF在模拟肺液（SLF）中的稳定性，并通过质谱（MS）和核磁共振（NMR）分析明确鉴定MF降解产物的结构。糠酸莫米松降解会生成两种产物，D1和D2，其生成具有显著的pH依赖性。在37摄氏度的SLF中，MF转化为D1以及随后D1转化为D2的半衰期分别为1.3小时和4.8小时。液相色谱 - 质谱联用（LC - MS）和核磁共振分析证实，D1是9,11 - 环氧糠酸莫米松，而D2代表一种在C17 - C21区域内显示环化的新化学结构。在大鼠肺糖皮质激素受体结合研究中评估了这些降解产物的生物活性。与地塞米松相比，D1对糖皮质激素受体的亲和力高4倍。然而，D2对受体的亲和力比地塞米松低一个对数级。MF在SLF中的不稳定性导致产生两种降解产物，其中一种降解产物显示出糖皮质激素受体活性，另一种代表一种尚未描述其药理特性的新环化结构。这些降解产物的生物学意义尚不清楚。
