A PAMPA Assay as Fast Predictive Model of Passive Human Skin Permeability of New Synthesized Corticosteroid C-21 Esters
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The permeation properties of twenty newly synthesized alpha-alkoxyalkanoyl and alpha-aryloxyalkanoyl C-21 esters of standard corticosteroids: Fluocinolone acetonide, dexamethasone, triamcinolone acetonide and hydrocortisone were established using a PAMPA assay (70% silicone oil and 30% isopropyl myristate). The data were compared with parent corticosteroids with addition of mometasone furoate and hydrocortisone acetate. All newly synthesized corticosteroid C-21 esters have effective permeability coefficients higher then -6, mostly followed with high values of retention factors and low permeation. The examined compounds were grouped through relationship between obtained retention factors and permeation parameters (groups I-III). The classification confirmed group I (membrane retentions as well as permeation lower then 30%) for all corticosteroid standards except mometasone furoate, a potent topical corticosteroid which, with high membrane retention (81%) and low permeation (7.7%) fits i...nto group III. The largest number of new synthesized corticosteroids C-21 esters, among them all fluocinolone acetonide C-21 esters, have high membrane retentions (32.4%-86.5%) and low permeations (1.3%-27.1%), fitting in group III. The classification was related to previously obtained anti-inflammatory activity data for the fluocinolone acetonide C-21 esters series. According to the PAMPA results the new synthesized esters could be considered as potential new prodrugs with useful benefit/risk ratio.
Keywords:corticosteroid C-21 esters / prodrug / PAMPA / membrane retention / permeation parameter
Source:Molecules, 2012, 17, 1, 480-491
- MDPI, Basel