UPTAKE AND METABOLISM OF CYCLOSPORINE-A AND SDZ IMM-125 IN THE HUMAN IN-VITRO SKIN(2TM) DERMAL AND BARRIER FUNCTION MODELS

Treatment of psoriasis with the immunosuppressant cyclosporin A (CSA) is beneficial orally but topical treatment is less efficacious. A comparison of CSA to its hydroxyethyl derivative SDZ IMM 125 (IMM) as to bioavailability to epidermal and dermal cells and the potential for inactivation by biotransformation was investigated using a human dermal skin model (skin(2)(TM) ZK1100) and a barrier function model (skin(2)(TM) ZK1300). The dermal ZK1100 model demonstrated that both cyclosporins could be metabolized by human dermis to the known primary hydroxylated metabolite, M17/AM1 for CSA and the hydroxylated analogue of IMM, IMM1. Application of the cyclosporins to the stratum corneum of the barrier function model ZK1300 demonstrated that both CSA and IMM would be bioavailable to the epidermal and dermal skin cells. Systemic concentrations would be expected to be low due to the slow permeation of the compounds and because mostly metabolites would reach the circulation. The difference between the two cyclosporins was the rate and extent of biotransformation with IMM metabolite formation being about 1/4 that of GSA.