IMMUNOSUPPRESSIVE ACTIVITY OF 13-CIS-RETINOIC ACID IN RATS - ASPECTS OF PHARMACOKINETICS AND PHARMACODYNAMICS

Pharmacokinetics and pharmacodynamics of 13-cis-retinoic acid (13-cRA) administered at doses that suppress experimental autoimmune encephalo myelitis (EAE) have been investigated in rats. Serum concentration of the drug measured following oral administration of 37 mg/kg/l2 h reach ed a peak of 1.8 x 10(-5) M in 2 h and linearly declined to 7.8 x 10(- 7) M at hour 12. When spleen cells (SC) collected from 13-cRA-administ ered animals were cultured in vitro, their proliferative response to t he T-cell mitogen concanavalin A (ConA) was suppressed and this effect was dependent on in vivo serum concentrations of the drug. In additio n, in vitro exposure of antigen-specific T-cell lines to 13-cRA concen trations equivalent to those observed in vivo caused a dose-dependent suppression of the proliferation induced by the antigen as well as by T-cell mitogens. On a molar basis, 13-cRA showed a stronger in vitro i mmunosuppressive activity than two immunosuppressive agents used in hu man therapy, cyclosporin A and 6-mercaptopurin. (C) 1997 Elsevier Scie nce B.V.