G M Ferron1, W J Jusko. 1. Department of Pharmaceutics, State University of New York at Buffalo, USA.
Abstract
PURPOSE: To assess pharmacokinetic and pharmacoimmunodynamic interactions between prednisolone (Pred, I1 mg/kg) and sirolimus (Sir, 0.25 mg/kg) in rabbits. METHODS: After intravenous administration, plasma concentrations of Pred and corticosterone, and Sir blood concentrations were followed for 24 hours along 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 Pred produced no changes. Corticosterone production (0-12hr) was suppressed by 55% after Pred alone or combined, while Sir did not cause adrenal suppression. Blood T-helper cells and granulocytes displayed circadian rhythms after placebo. Over 12 hr, T-helper cell counts were decreased by Pred (40%) and Sir (19%) while granulocyte numbers increased by 56% and 23%. After coadministration, cell numbers were similar to Pred alone. Pred and Sir decreased lymphocyte reactivity by 41% and 56% over 24 hr and their combination reached 85% inhibition with additive interaction. In vitro studies showed antagonistic or synergistic interactions depending on drug concentration ratios. CONCLUSIONS: At therapeutic concentrations, Sir and Pred do not significantly interact pharmacokinetically and have additive pharmacoimmunodynamics. Thus, the therapeutic application of this combination is promising.
PURPOSE: To assess pharmacokinetic and pharmacoimmunodynamic interactions between prednisolone (Pred, I1 mg/kg) and sirolimus (Sir, 0.25 mg/kg) in rabbits. METHODS: After intravenous administration, plasma concentrations of Pred and corticosterone, and Sir blood concentrations were followed for 24 hours along 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 Pred produced no changes. Corticosterone production (0-12hr) was suppressed by 55% after Pred alone or combined, while Sir did not cause adrenal suppression. Blood T-helper cells and granulocytes displayed circadian rhythms after placebo. Over 12 hr, T-helper cell counts were decreased by Pred (40%) and Sir (19%) while granulocyte numbers increased by 56% and 23%. After coadministration, cell numbers were similar to Pred alone. Pred and Sir decreased lymphocyte reactivity by 41% and 56% over 24 hr and their combination reached 85% inhibition with additive interaction. In vitro studies showed antagonistic or synergistic interactions depending on drug concentration ratios. CONCLUSIONS: At therapeutic concentrations, Sir and Pred do not significantly interact pharmacokinetically and have additive pharmacoimmunodynamics. Thus, the therapeutic application of this combination is promising.