METABOLISM OF TESTOSTERONE AND ITS ESTER DERIVATIVES IN ORGANOTYPIC COCULTURE OF HUMAN DERMAL FIBROBLASTS WITH DIFFERENTIATED EPIDERMIS

The metabolism of testosterone (TS) and its 17-O-acyl derivatives (acy l = acetyl, benzoyl and hemi-succinoyl) was studied using radioactive compounds in organotypic coculture of human dermal fibroblasts (living skin equivalent, LSE). When TS was applied to the epidermal-side of L SE in a small volume of acetone solution, both 5 alpha-reduced and 17- dehydrogenated metabolites were observed in the dermal-side culture so lution, though the formation of the 5 alpha-reduced metabolites, dihyd rotestosterone (DHT) and dihydroandrosterone (DHA), depended greatly o n the culture conditions. The metabolic activity of LSE for testostero ne was higher than that of excised hairless-rat skin. The metabolism o f ester prodrugs of TS in LSE was dependent on their physicochemical p roperties and susceptibility to enzymatic hydrolysis. Application of a cetyl-TS and benzoyl-TS resulted in a high formation of the 17-dehydro genated metabolite, androstenedione (ADO), though avery small amount o f the prodrug was observed in the dermal side. Succinoyl-TS, a hydroph ilic ester with very low susceptibility to hydrolysis, was quite resis tant to both 5 alpha-reduction and 17-dehydrogenation, and more than 9 0% of the radioactivity appearing on the dermal side was from the prod rug itself and from TS. The hydrophilic and enzymatically stable TS de rivative may be a good candidate compound with which to administer TS transdermally.