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 mononuclear cells (PBMCs) that exhibit resistance to cyclosporine (INN, ciclosporin) or glucocorticoids in vitro are refractory to therapy based on these drugs in vivo. However, detection or distribution of the resistant patients with immunologic disorders remains to be documented.


METHODS
Drug sensitivity tests were performed with PBMCs from four subject groups: 69 healthy subjects, 100 patients with chronic renal failure, 38 patients with nephrosis, and 51 patients with psoriasis. The values for the concentration that produces 50% lymphocyte-mitosis inhibition (IC50) of the drugs on PBMC blastogenesis were estimated, and individual variations or group differences in the IC50 values were examined.


RESULTS
The median cyclosporine IC50 values of the four subject groups were similar, but large individual deviations in the IC50 values 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 failure group exhibited low responses to prednisolone (p < 0.04). In contrast, no significant difference in the methylprednisolone IC50 was observed among the groups. Normal upper thresholds for IC50 values of these drugs were estimated from the mean + 2 standard deviations (SD) of the IC50 values of healthy PBMCs, and the patients with IC50 values above these levels were considered to be resistant. The incidence of resistant patients with nephrosis or psoriasis was similar to that of healthy subjects; however, the incidence of cyclosporine- or prednisolone-resistant subjects with chronic renal failure was significantly higher (p < 0.04). Significant correlations between PBMC sensitivity to cyclosporine in vitro and clinical efficacy of the drug in vivo were observed in renal transplant recipients and in patients with psoriasis.


CONCLUSIONS
A large subset of patients with chronic renal failure showed PBMC resistance to cyclosporine and prednisolone. Hyperresistant patients have a high risk of being refractory to immunosuppressive therapy with one of these drugs. Alternative treatment should be considered according to the individual drug-sensitivity data.
Hirano
T
T
Department of Clinical Pharmacology, Tokyo College of Pharmacy, Japan. hiranot@ps.toyaku.ac.jp
Oka
K
K
Takeuchi
H
H
Kozaki
K
K
Matsuno
N
N
Nagao
T
T
Kozaki
M
M
Ichikawa
M
M
Yoshida
M
M
Umezawa
Y
Y
Hirata
M
M
Oh-i
T
T
Koga
M
M
D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007676:Kidney Failure, Chronic / Q000097:blood / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D008875:Middle Aged; D009401:Nephrosis / Q000097:blood / Q000276:immunology*; D011239:Prednisolone / Q000494:pharmacology; D011565:Psoriasis / Q000097:blood / Q000276:immunology*
D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011239:Prednisolone; D008775:Methylprednisolone