BLOOD DISTRIBUTION OF RAPAMYCIN

Rapamycin (RAPA) is a potent new immunosuppressive drug. Although bloo d concentration monitoring of RAPA is being performed in preclinical a nd clinical trials, little is known regarding the blood distribution o f the drug. Such information would have an impact on the medium used f or analysis of the drug. The distribution of RAPA was investigated by spiking human whole blood having an initial temperature of either 4 de grees C or 22 degrees C with a constant amount of H-3-RAPA and increas ing amounts of RAPA to a final concentration of 5-100 mu g/L. The drug concentration spans the range seen when immunosuppressive doses of th e drug are administered. This was followed by incubation of the blood at 37 degrees C for 0 to 60 min before separation of cells. The dpm in the resulting plasma and RBC fractions was determined by scintillatio n counting. The plasma to formed blood elements and plasma to whole bl ood ratios were 0.05+/-0.051 and 0.09+/-0.016, respectively (mean +/- SD, n=50). The distribution did not exhibit any temperature or concent ration dependence. The proportion of the drug among cellular component s was as follows (mean % distribution +/- SD); RBC 94.5+/-4.9%; plasma 3.1+/-2.5%; lymphocytes 1.01+/-1.02%; and granulocytes 1.0+/-0.88%. T he free or unbound fraction of RAPA over the plasma concentration rang e of 5-100 mu g/L as determined by ultracentrifugation was 2.5+/-0.2%. The drug was found to be associated primarily with nonlipoprotein fra ctions in plasma. The results suggest from an analytical perspective t hat whole blood as compared with plasma would be the most suitable med ium for analysis due to the higher concentrations found in the former.