Pharmacokinetic and pharmacoimmunodynamic interactions between prednisolone and sirolimus in adrenalectomized rats

Prednisolone (Pred) and sirolimus (SIR) are immunosuppressive compounds act ing through different mechanisms with moderate synergism found in vitro. Bo th drugs are metabolized partly by CYP3A enzymes. After iv administration o f placebo, Pred (5 mg/kg), SIR (1 mg/kg), ol Pred with SIR (5 and 1 mg/kg d oses) to adrenalectomized male rats, Pied plasma and SIR whole blood concen trations were followed for 48 hr along with circulating T-helper and T-cyto toxic cell counts. Ex vivo whole blood lymphocyte proliferation marked host responsiveness. An extended indirect PK/PD model was used to describe resp onses to these drugs, alone or combined. An interactive two-stage populatio n analysis showed no modification in dug PK. Mean Pred plasma clearance was 0.655 L/hr (interrat variability: 11%) and significantly increased with we ight. Mean SIR whole blood volume of distribution and clearance were 5.6 L (62%) and 0.28 L/hr (32%), and animal scaling showed weight(power) proporti onality. In vitro metabolism studies showed no significant inhibition of Pr ed or prednisone CYP3A metabolism by SIR (50 mu M), but this pathway accoun ted for less than 5% of Pled metabolism. Pled decreased numbers of T-helper lymphocytes with a mean IC50 of 37.8 nM (21%) alone or 12.3 nM (130%) with SIR. Results for T-cytotoxic lymphocytes were similar. SIR increased lymph ocyte numbers with a mean IC50 of 52.2 nM (24%) for T-helper and 28.8 nM (5 1%) for T-cytotoxic cells. Taking into account drug effects on lymphocyte t rafficking, Pred directly inhibited ex vivo lymphocyte proliferation with a mean IC50 of 1.08 nM (38%). SIR, after a transduction step, inhibited prol iferation with a mean IC50 of 1.00 nM (26%). Responses measured after dug c oadministration were reasonably quantitated by addition of single drug effe cts. Since, at pharmacologic concentrations in rats, Pred and SIR did not i nteract in their PK but synergistically or additively interact in their dyn amics, their joint therapeutic use is promising. The adrenalectomized rat m ay be a suitable animal model to characterize drug effects on lymphocyte tr afficking and reactivity.