DISTRIBUTION CHARACTERISTICS OF IMMUNOSUPPRESSANTS FK506 AND CYCLOSPORINE-A IN THE BLOOD COMPARTMENT

Using two representative immunosuppressants, FK506 (FK) and cyclospori n A (CyA), of which the mechanism of pharmacological action is the sam e although there is a great difference in the pharmacological intensit y, the distribution characteristics were studied in both in vivo and i n vitro experiments using rat, dog, and human blood. Blood samples wer e fractionated by means of sedimentation in Ficoll-Paque(R), and the d rug contents in the diluted plasma fraction, erythrocyte fraction, and lymphocyte fraction were measured by an HPLC method. FK distributes t o the lymphocyte fraction to a level about three times greater than th at of CyA, while CyA distributes to the erythrocyte fraction to a leve l ten times that of FK. The distribution pattern of these fractions wa s independent of the drug concentration and species after correcting t he drug concentration in each fraction with the blood drug concentrati on. The uptakes of FK and CyA in the isolated lymphocytes obtained fro m the rat spleen and human peripheral blood were also studied. The amo unt of FK taken up by the spleen lymphocytes is five times greater tha n that of CyA. In the case of the uptake study using human peripheral blood lymphocytes, the concentration of FK in the lymphocyte is 100-fo ld higher than that of CyA. This difference in the lymphocyte level be tween the two immunosuppressants is thought to be one of the reasons w hy FK is more potent than CyA, a difference of about 100-fold in the i n vitro pharmacological study and about tenfold in the in vivo organ t ransplantation experiments.