Implication of cholesterol in cyclosporine pharmacodynamics in minimal change nephrotic syndrome.
BACKGROUND
High blood cholesterol concentrations in patients with minimal change nephrotic syndrome may affect cyclosporine (INN, ciclosporin) pharmacodynamics and its clinical efficacy, but few attempts have been carried out to disclose this problem.


METHODS
We evaluated the cellular pharmacodynamics of cyclosporine in 24 patients with minimal change nephrotic syndrome. In vitro cyclosporine concentrations yielding 50% inhibition (IC(50)) of blastogenesis of peripheral blood mononuclear cells (PBMCs) stimulated with concanavalin A were calculated. The relationships between the IC(50) values and laboratory data including serum total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol concentrations were examined. Clinical cyclosporine efficacy was assessed by a decreasing rate (percentage) of urinary protein 1 week after cyclosporine therapy. Percentages of LDL receptor-positive or CD3-positive PBMCs were evaluated with flow cytometry in 7 patients and 15 healthy subjects.


RESULTS
The cyclosporine IC(50) values negatively correlated with the clinical cyclosporine efficacy assessed by a decreasing rate of urinary protein (r = -0.708, P =.0006). Cyclosporine IC(50) values significantly correlated with either serum total cholesterol (r = 0.681, P =.0003) or LDL cholesterol (r = 0.751, P =.0034) concentrations. Furthermore, serum total or LDL cholesterol levels significantly correlated negatively with clinical cyclosporine efficacy (r = -0.613, P =.0057, and r = -0.773, P =.0399, respectively). In 7 patients, serum total and LDL cholesterol concentrations were significantly higher than those of 15 healthy subjects (P <.005), whereas the percentages of LDL receptor-expressing cells in CD3-enriched PBMCs were not significantly different between these patients and healthy subjects. In addition, the cyclosporine IC(50) values and the percentages of LDL receptor-expressing PBMCs did not negatively correlate in either the patients or the healthy subjects.


CONCLUSIONS
The data raised the possibility that hypercholesterolemia in patients with minimal change nephrotic syndrome attenuates cellular and clinical cyclosporine pharmacodynamics. Down-regulation of LDL receptor in T cells was not observed in these patients, and individual deviation of PBMC response to cyclosporine does not appear to be related to the difference of LDL receptor-positive cell numbers.
Hirano
Toshihiko
T
Department of Clinical Phar-macology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. hiranot@ps.toyaku.ac.jp
Kawamura
Tomoe
T
Fukuda
Sachiko
S
Kohsaka
Satoshi
S
Yoshikawa
Noriko
N
Yoshida
Masaharu
M
Oka
Kitaro
K
D000328:Adult; D000704:Analysis of Variance; D016022:Case-Control Studies; D002784:Cholesterol / Q000097:blood*; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009402:Nephrosis, Lipoid / Q000378:metabolism*
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D002784:Cholesterol