Species- and gender-related differences in cyclosporine/prednisolone/sirolimus interactions in whole blood lymphocyte proliferation assays

Cyclosporin A (CyA), prednisolone (Pred) and sirolimus (Sir) inhibit lymphocyte proliferation at the cytokine transcription (CyA and Pred) or signal transduction (Sir) levels. Their double and triple Interactions were studied on lectin-induced proliferation of whole blood lymphocytes (WBLP) from male and female humans, rabbits and rats. Isobols along with the Universal Response Surface Approach were used to describe and quantify the nature and intensity of drug interactions by determining α 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 action (l(max) = 67%) and rats were more sensitive to Pred (IC₅₀ = 9.1 nM in females) and Sir (2.8 nM) actions than humans (32 and 55 nM). Gender differences were observed but were not consistent across species. All double-drug combinations were synergistic, and combinations containing Pred were 10 to 100 times more synergistic in rabbits (α(Pred/Sir) = 213 and α(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 α values were able to describe CyA/Pred/Sir triple combination effects. These studies indicate that CyA, Pred and Sir act and synergistically interact in vitro in species- and gender-dependent fashions. Adrenalectomized rats better resemble humans in these responses. WBLP are useful in various species in determining immunosuppressive drug action and interactions.