The penetration and absorption of tacrolimus (FK506) in the skin of rat after a single topical ap plication of 14C-labeled FK506 (14C-FK506) ointment under occlusive dressing was studied by semi microautoradiography of the skin and by counting radioactivity in the sliced sections of the skin. Stability of FK506 in the skin was investigated in vivo and in vitro. 1. The distribution of the radioactivity of 14C-FK506 in rat skin was observed by semi-microau toradiography after a single dermal

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... cation of the ointment. In the intact skin, radioactivity of the oint ment was mainly distributed in the stratum corneum of the epidermis during application for 24 hours. In the damaged skin, radioactivity was observed in the epidermis and dermis after application for 2 hours, and was evenly distributed in the dermis and subcutaneous connective tissues after application for 8 hours. Radioac tivity was detected in the hair follicles of both the intact and damaged skin, but that was negligible in the se baceous gland of the intact skin or was less than in the follicles of the damaged skin. 2. After a single dermal application of 14C-FK506 ointment to rats, the penetration of FK506 was inves tigated by counting radioactivity in the sliced section of skin. In the intact skin, maximal radioactivity was observed in the section of the epidermis throughout the application period for 24 hours. In the damaged skin, maximal radioactivity was detected in the dermis after application for 2 hours, and radioactivity in the sections was decreased thereafter and only a small amount of radioactivity was observed after application for 24 hours. 3. After application of 14C-FK506 ointment for 24 hours, levels of radioactivity were compared with those of FK506 in the skin, and the unchanged FK506 accounted for about 90% of radioactivity detected.4 . The oxidative metabolism of FK506 was studied in the skin and liver microsomes. Formation of the in vitro major metabolite, the 13-O-demethylated metabolite, in the skin microsomes was several-fold less intensive than in the liver microsomes.