IMMUNOSUPPRESSANT PHARMACODYNAMICS ON LYMPHOCYTES FROM HEALTHY-SUBJECTS AND PATIENTS WITH CHRONIC-RENAL-FAILURE, NEPHROSIS, AND PSORIASIS -POSSIBLE IMPLICATIONS FOR INDIVIDUAL THERAPEUTIC EFFICACY

Background: In organ transplantation, patients with peripheral blood m ononuclear cells (PBMCs) that exhibit resistance to cyclosporine (INN, cidosporin) or glucocorticoids in vitro are refractory to therapy bas ed on these drugs in vivo. However, detection or distribution of the r esistant patients with immunologic disorders remains to be documented. Methods: Drug sensitivity tests were performed with PBMCs from four s ubject groups: 69 healthy subjects, 100 patients with chronic renal fa ilure, 38 patients with nephrosis, and 51 patients with psoriasis, The values for the concentration that produces 50% lymphocyte-mitosis inh ibition (IC50) of the drugs on PBMC blastogenesis were estimated, and individual variations or group differences in the IC50 values were exa mined, Results: The median cyclosporine IC50 values of the four subjec t groups were similar, but large individual deviations in the IC50 val ues were observed, Individual differences in prednisolone IC50 values were spread from 1 to 3500 ng/ml, When compared with healthy subjects, a significantly large number of the patients with chronic renal failu re group exhibited low responses to prednisolone (P < 0.04). In contra st, no significant difference in the methylprednisolone IC50 was obser ved among the groups, Normal upper thresholds for IC50 values of these drugs were estimated from the mean + 2 standard deviations (SD) of th e IC50 values of healthy PBMCs, and the patients with IC50 values abov e these levels were considered to be resistant. The incidence of resis tant patients with nephrosis or psoriasis was similar to that of healt hy subjects; however, the incidence of cyclosporine-or prednisolone-re sistant subjects with chronic renal failure was significantly higher ( p < 0.04). Significant correlations between PBMC sensitivity to cyclos porine in vitro and clinical efficacy of the drug in vivo were observe d in renal transplant recipients and in patients with psoriasis. Concl usions: A large subset of patients with chronic renal failure showed P BMC resistance to cyclosporine and prednisolone. Hyperresistant patien ts have a high risk of being refractory to immunosuppressive therapy w ith one of these drugs. Alternative treatment should be considered acc ording to the individual drug-sensitivity data.