DISTRIBUTION OF SIROLIMUS IN RAT-TISSUE

Objectives: To examine the distribution of sirolimus (SRL, rapamycin), an immunosuppressive macrolide antibiotic, in the tissues of adult ma le Wistar-Furth rats following continuous intravenous infusion (CIVI) and repeated daily peroral gavage (PO). Design and Methods: Animals re ceived 14-day courses of SRL by either CIVI (0.04-0.4 mg/kg/day) or PO (0.4-1.6 mg/kg/day) administration. Samples of whole blood and homoge nates of five solid organs (heart, kidney, liver, lung and spleen), an d portions of intestinal, muscle and testicular tissues were prepared on day 13 of CIVI treatment or 24 hours after administration of the 14 th PO dose. SRL concentrations were determined by high performance liq uid chromatography with reference to calibration curves produced from SRL-spiked whole blood or tissue homogenates prepared from drug-free a nimals. Results: Following PO but not CIVI administration, SRL concent rations in whole blood and all tissues increased linearly in relation to dose. SRL was extensively distributed among most tissues tested (ti ssue partitions coefficients of >40 were observed in some cases). Comp aratively, SRL whole blood concentrations were low. The ratio between the SRL whole blood concentrations after PO versus after CIVI administ ration (at like doses of 0.4 mg/kg/day) was 0.04. Therefore, we inferr ed that the oral bioavailability of SRL was low. Conclusions: The line ar relationships between PO dose and SRL concentrations in whole blood and tissues may be attributed to the low oral bioavailability of SRL, which is indicated by the low levels of SRL observed in whole blood a nd tissues after PO administration. The nonlinear relationships betwee n CIVI dose and SRL concentrations in whole blood and tissues may resu lt because although whole blood depots may be saturated with SRL, the tissues continue to absorb SRL as the dose of SRL increases. Thus, bec ause a high percentage of SRL is widely distributed into tissue stores , caution must be used when administering this drug in humans.