A PAMPA assay as fast predictive model of passive human skin permeability of new synthesized corticosteroid C-21 esters.
The permeation properties of twenty newly synthesized α-alkoxyalkanoyl and α-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 into 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.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia. bojan@pharmacy.bg.ac.rs
Bojan D
BD
Markovic
Sote M
SM
Vladimirov
Olivera A
OA
Cudina
Jadranka V
JV
Odovic
Katarina D
KD
Karljikovic-Rajic
D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry* / Q000592:standards; D006801:Humans; D008567:Membranes, Artificial; D008954:Models, Biological; D009226:Myristates / Q000737:chemistry; D010539:Permeability; D011278:Pregnanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000592:standards; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000592:standards; D012015:Reference Standards; D012827:Silicone Oils / Q000737:chemistry; D012869:Skin Absorption
D004952:Esters; D008567:Membranes, Artificial; D009226:Myristates; D011278:Pregnanes; D011355:Prodrugs; D012827:Silicone Oils; C008205:isopropyl myristate