COMPARATIVE IN-VITRO SKIN ABSORPTION AND METABOLISM OF COUMARIN (1,2-BENZOPYRONE) IN HUMAN, RAT, AND MOUSE

The in vitro percutaneous absorption and skin metabolism of coumarin ( 1,2-benzopyrone) was studied in metabolically viable human, rat (F344) , and mouse (CD1 and DBA/2) skin. Following application of [C-14]couma rin (3.7 mu g/cm(2); 0.02% in ethanol) to unoccluded skin in flow-thro ugh diffusion cells of a skin absorption model (SAM), the absorption t hrough the skin into the receptor fluid at 72 hr was rapid and extensi ve in all species, reaching (mean +/- SD) 50.4 +/- 9.1% of the applied dose in human, 51.3 +/- 7.3% in rat, and 44.9 +/- 13.5% in mouse. Whe n the skin was occluded immediately after exposure, the extent of abso rption at 72 hr was enhanced in all species. At 72 hr, substantial amo unts of [C-14]coumarin were found in unoccluded mouse skin (31.7 +/- 1 3.6%), with less in human (10.2 +/- 6.5%) and rat (12.7 +/- 5.0%) tiss ue. When occluded, the skin residues at 72 hr were 10.4 +/- 11.7% (mou se), 8.5 +/- 3.9% (human), and 11.9 +/- 7.5% (rat). The absorption of coumarin through rat skin into the receptor fluid over 72 hr was linea rly related to the applied dose (r(2) = 0.998 unoccluded skin; r(2) = 0.999 occluded skin) over the dose range 3.7 to 378.7 mu g/cm(2). The nature and extent of cutaneous metabolism was studied following (i) to pical application for 24 hr to human, rat, and mouse skin in the SAM s ystem; (ii) incubation at 37 degrees C for up to 6 hr with human, rat, and mouse whole skin homogenates; and (iii) incubation at 37 degrees C for up to 24 hr with freshly isolated and cultured human epidermal k eratinocytes. HPLC and GCMS analyses of skin extracts and receptor flu id confirmed that, in all three species, only the parent compound, cou marin, was present at all times from 10 min to 24 hr. These data indic ate that topically applied coumarin is rapidly and extensively absorbe d through human, rat, and mouse skin, and that the compound remains me tabolically unchanged during absorption. These observations may have i mplications for the safe and effective use of coumarin in consumer pro ducts which come into contact with the skin and as a topical therapeut ic agent. (C) 1997 Academic Press.