Percutaneous absorption of methotrexate: effect on epidermal DNA synthesis in hairless mice

One of the presumed reasons for the lack of clinical activity of topical methotrexate in psoriasis is insufficient percutaneous penetration necessary to inhibit epidermal DNA synthesis. The present study was undertaken to select a vehicle to optimize penetration of methotrexate in vitro and to determine the effects of this topical formulation on epidermal DNA synthesis in vivo in hairless mouse skin. Increased penetration of methotrexate was obtained in human skin in vitro with Vehicle N compared to water and n-decylmethylsulfoxide vehicles. Repeated topical application of this methotrexate/Vehicle N preparation produced marked epidermal atrophy in treated sites in both normal and hyperproliferative essential fatty acid deficient hairless mouse skin without similar effects at a distant skin site. Local inhibition of epidermal DNA synthesis was also obtained without systemic effects at a distant site. These studies demonstrate that methotrexate in Vehicle N may produce a direct effect on epidermis which may be useful for the topical therapy of psoriasis.