Prospects for future topical glucocorticoid development.
Current glucocorticoids are inactivated mainly in the liver. Results from studies of their catabolism; their concentration gradients in epidermis and upper and lower dermis after topical application to intact and injured skin; and the concentration needed to inhibit synthesis of human connective tissue by skin fibroblasts; suggest that their systemic and local adverse reactions would logically be reduced further by adding a rapid extrahepatic biotransformation. An ideal glucocorticoid should be locally inactivated during, or immediately after, absorption. The data available for three glucocorticoids with some extrahepatic metabolism suggest that such relatively labile steroids may have a more autoregulating absorption than that of the conventional, more stable, steroids. This means that in skin areas with a damaged stratum corneum, the balance between steroid influx and inactivation may favour anti-inflammatory activity, while that balance is insufficient in intact skin for a triggering of glucocorticosteroid activity. When the skin lesions heal, and the high influx rate tapers off, corticosteroid activity in the epidermis and dermis may be better cut off than with the conventional, metabolically stable, corticosteroids. The compounds subject to local metabolism available today appear to have only moderate topical corticosteroid activity. There are still no valid data to support a claim that their catabolic effects on the connective tissue of diseased skin are less than those of conventional topical steroids. However, novel glucocorticosteroids with a still better relation between high intrinsic glucocorticosteroid activity and rapid metabolic turnover in skin should be designed and tested.
Brattsand
R
R
Research and Development Department, AB Draco, Lund, Sweden.
Särnstrand
B
B
D000287:Administration, Topical; D000893:Anti-Inflammatory Agents / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics; D001284:Atrophy; D001711:Biotransformation; D019819:Budesonide; D002254:Carbonates / Q000378:metabolism; D002264:Carboxylic Acids / Q000378:metabolism / Q000627:therapeutic use; D003238:Connective Tissue / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D005544:Forecasting; D005938:Glucocorticoids; D006801:Humans; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000187:drug effects; D011282:Pregnenediones / Q000378:metabolism / Q000493:pharmacokinetics; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013329:Structure-Activity Relationship; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D002254:Carbonates; D002264:Carboxylic Acids; D005938:Glucocorticoids; D011282:Pregnenediones; D019819:Budesonide