title: Pharmacokinetic and pharmacoimmunodynamic interactions between prednisolone and sirolimus in rabbits.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmaceutics, State University of New York at Buffalo, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Ferron
authors.forename: W J
authors.initials: WJ
authors.lastname: Jusko
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D003345:Corticosterone / Q000097:blood; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D011239:Prednisolone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011817:Rabbits; D020123:Sirolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D011239:Prednisolone; D020123:Sirolimus; D003345:Corticosterone