Pharmacokinetic and pharmacoimmunodynamic interactions between prednisolone and sirolimus in rabbits

Purpose. To assess pharmacokinetic and pharmacoimmunodynamic interactions b etween prednisolone (Pred, 1 mg/kg) and sirolimus (Sir, 0.25 mg/kg) in rabb its. Methods. After intravenous administration, plasma concentrations of Pred an d corticosterone, and Sir blood concentrations were followed for 24 hours a long with blood granulocyte and T-helper cell counts. Ex vivo and in vitro whole blood lymphocyte proliferation marked lymphocyte reactivity. Results. Pred terminal half-life and clearance were 1.1 hr and 0.72 l/hr/kg with no difference after Sir. Sir values were 13 hr and 0.16 l/hr/kg and P red produced no changes, Corticosterone production (0-12 hr) was suppressed by 55% after Pred alone or combined, while Sir did not cause adrenal suppr ession. Blood T-helper cells and granulocytes displayed circadian rhythms a fter placebo. Over 12 hr, T-helper cell counts were decreased by Pred (40%) and Sir (19%) while granulocyte numbers increased by 568 and 23%. After co administration, cell numbers were similar to Pred alone. Pred and Sir decre ased lymphocyte reactivity by 41% and 56% over 24 hr and their combination reached 85% inhibition with additive interaction. In vitro studies showed a ntagonistic or synergistic interactions depending on drug concentration rat ios. Conclusions, At therapeutic concentrations, Sir and Pred do not significant ly interact pharmacokinetically and have additive pharmacoimmunodynamics. T hus, the therapeutic application of this combinaison is promising.