ANTIINFLAMMATORY EFFECTS OF MACROPHILIN-INTERACTING DRUGS IN ANIMAL-MODELS OF IRRITANT AND ALLERGIC CONTACT-DERMATITIS

The macrolide antibiotics, FK 506 and rapamycin, have been reported to be potent immunosuppressive drugs. Both FK 506 and rapamycin bind to the immunophilin macrophilin-12. Rapamycin, however, acts on T cells by a different mode of action which does not affect the transcription of lymphokines. The anti-inflammatory effects of FK 506 and rapamycin have been tested in mouse models of irritant dermatitis after topical application, and in allergic contact dermatitis after topical or oral application, using mice and domestic pigs. In irritant dermatitis, both FK 506 and rapamycin exerted significant, but moderate topical activity at concentrations of 0.4-3.6%. In allergic contact dermatitis, topical FK 506 proved to be highly active at concentrations of 0.01-0.1% and even superior to corticosteroids. In contrast, rapamycin was inactive. After oral treatment of mice, FK 506 was significantly active (2 x 30 mg/kg/day) while rapamycin was inactive up to the highest dose tested (2 x 90 mg/kg/day). These results indicate that, despite the chemical similarity of FK 506 and rapamycin and their common intracellular receptor, there are different fundamental pharmacological properties of FK 506 and rapamycin, which may reflect their different modes of action.