SPECIES-RELATED AND GENDER-RELATED DIFFERENCES IN CYCLOSPORINE PREDNISOLONE/SIROLIMUS INTERACTIONS IN WHOLE-BLOOD LYMPHOCYTE-PROLIFERATION ASSAYS/

Cyclosporin A (CyA), prednisolone (Pred) and sirolimus (Sir) inhibit l ymphocyte proliferation at the cytokine transcription (CyA and Pred) o r signal transduction (Sir) levels. Their double and triple interactio ns were studied on lectin-induced proliferation of whole blood lymphoc ytes (WBLP) from male and female humans, rabbits and rats. Isobols alo ng with the Universal Response Surface Approach were used to describe and quantify the nature and intensity of drug interactions by determin ing a values. CyA was always less potent than Pred and Sir while these two compounds were relatively equipotent. Species-related differences were observed with single drugs. Rabbit WBLP were resistant to Pred a ction (I-max = 67%) and rats were more sensitive to Pred (IC50 = 9.1 n M in females) and Sir (2.8 nM) actions than humans (32 and 55 nM). Gen der differences were observed but were not consistent across species. All double-drug combinations were synergistic, and combinations contai ning Pred were 10 to 100 times more synergistic in rabbits (alpha(Pred /Sir) = 213 and alpha(CyA/Pred) = 147 in males) than in rats (12 and 2 .1) or humans (3.7 and 5.7) in relation to the lower efficacy of Pred. Double-combination ar values were able to describe CyA/Pred/Sir tripl e combination effects. These studies indicate that CyA, Pred and Sir a ct and synergistically interact in vitro in species- and gender-depend ent fashions. Adrenalectomized rats better resemble humans in these re sponses. WBLP are useful in various species in determining immunosuppr essive drug action and interactions.