title: Development of glucocorticosteroids with enhanced ratio between topical and systemic effects.
abstract: A high potency at the application site and a low incidence of glucocorticoid side-effects form the desired profile of glucocorticosteroids for anti-inflammatory therapy. A new type of glucocorticosteroid 16,17-acetals with an improved topical/systemic activity ratio has been developed. Non-symmetric 16,17-acetal substitution increased the topical anti-inflammatory activity more than the systemic activity in rodents, whereas fluorine substitution in 9 alpha- or 6 alpha,9 alpha-positions increased the systemic more than the topical potency. The non-fluorinated, non-symmetric 16 alpha,17 alpha-acetal budesonide reached the highest ratio, which was five to ten times better than that of the earlier known 16,17-acetonides such as triamcinolone acetonide, or that of the 17 alpha-esters such as beclomethasone 17 alpha,21-dipropionate. Although budesonide and betamethasone 17 alpha,21-diproprionate have the same topical anti-inflammatory potency, the latter decreased plasma and urinary cortisol levels significantly more when ointment preparations were compared in volunteers. Budesonide is efficiently biotransformed in the liver to metabolites such as 6 beta-hydroxybudesonide and 16 alpha-hydroxyprednisolone, which are 50-100 times less potent than the parent steroid. In homogenates of rat or human adult livers budesonide is biotransformed two to five times more rapidly than desonide and triamcinolone acetonide.
authors.affiliation: Research and Development Department, AB Draco, Lund, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Thalén
authors.forename: R
authors.initials: R
authors.lastname: Brattsand
authors.forename: P H
authors.initials: PH
authors.lastname: Andersson
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001623:Betamethasone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D001624:Betamethasone Valerate / Q000008:administration & dosage / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D019819:Budesonide; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D011282:Pregnenediones / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D011282:Pregnenediones; C007975:hydrocortisone-17-butyrate; D019819:Budesonide; C011175:betamethasone-17,21-dipropionate; D001623:Betamethasone; D001624:Betamethasone Valerate; D006854:Hydrocortisone