Long chain fatty acid conjugation remarkably decreases the aggregation induced toxicity of Amphotericin B

Publication date: 10 June 2018 Source:International Journal of Pharmaceutics, Volume 544, Issue 1 Author(s): Kaushik Thanki, Rameshwar Prajapati, Abhay T. Sangamwar, Sanyog Jain Amphotericin B is an antimicrobial membrane-acting drug used in the treatment of systemic fungal infections. However, the clinical utility of AmB is often low as a result of (i) dose-limiting toxicity which is closely associated with its aggregation wherein the selectivity for its target i.e. ergosterol in fungal membranes is diminished and (ii) limited oral bioavailablity. The latter is attributed to the unfavorable physicochemical properties of the AmB e.g., low solubility, gastrointestinal instability, and poor intestinal permeability. The hypothesis of present work was that by applying a lipid conjugation approach the aggregation induced toxicity of AmB vis-à-vis permeability can be overcome. From the array of fatty acids, the oleic acid (OA) was selected for conjugation due to its great impact on increasing the Caco-2 permeability of AmB. AmB-OA conjugate was synthesized using standard carbodiimide chemistry and characterized thoroughly. Due to the reported strong correlation between the self-aggregation of AmB and toxicity, the aggregation behavior of AmB and AmB-OA was studied by in silico modeling and confirmed experimentally. In vitro hemolytic studies and viability assays in kidney cells (HEK 293 cells) suggested that AmB in aggregated was state highly toxic but not AmB-OA. In silico ...
Source: International Journal of Pharmaceutics - Category: Drugs & Pharmacology Source Type: research