Comparative study of the cellular pharmacodynamics of calcineurin inhibitors between patients with chronic renal failure awaiting renal transplantation and cirrhosis patients awaiting liver transplantation.
The in vitro response of peripheral blood mononuclear cells (PBMCs) to the suppressive effects of calcineurin inhibitors is known to correlate with the clinical efficacy of drugs used in renal transplantations. The present study was conducted to examine the differences of PBMC responses to calcineurin inhibitors between chronic renal failure (CRF) patients awaiting renal transplantation and cirrhosis patients awaiting liver transplantation. The study included 99 CRF patients awaiting renal transplantation and 27 cirrhosis patients awaiting liver transplantation. Twenty milliliters of venous blood was taken 1-7 days before transplantation. The in vitro drug concentrations giving 50% inhibition of PBMC blastogenesis stimulated with concanavalin A (IC(50)s) were calculated. The suppressive effects of tacrolimus against PBMC blastogenesis were more than 10-100 times stronger than those of cyclosporine. The median IC(50) value for cyclosporine against the CRF PBMCs was not significantly different from the median IC(50) value against the cirrhosis PBMCs. In contrast, tacrolimus sensitivity in cirrhosis PBMCs is approximately seven times higher than that in CRF PBMCs. The median IC(50) value for tacrolimus against cirrhosis PBMCs was significantly lower and therefore the effect was stronger in comparison to the CRF PBMCs (p < 0.001). These data suggest that the PBMCs of cirrhosis patients, in comparison to those of CRF patients, are highly sensitive to the suppressive effect of tacrolimus. However, PBMC sensitivity to cyclosporine was not significantly different between the CRF and cirrhosis patients. These observations raise the possibility that treatment with tacrolimus, rather than cyclosporine, may therefore be a better choice to reduce the risks of allograft rejection in liver transplantation.
Department of 5th Surgery, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.
Yu
Y
Kihara
Naoto
N
Matsuno
Abuduxukuer
A
Mijiti
Takeshi
T
Nagao
Hironori
H
Takeuchi
Sakae
S
Unezaki
Toshihiko
T
Hirano
D000368:Aged; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D003208:Concanavalin A / Q000378:metabolism; D016572:Cyclosporine / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000276:immunology; D016030:Kidney Transplantation; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000276:immunology; D016031:Liver Transplantation; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D016559:Tacrolimus / Q000627:therapeutic use
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D003208:Concanavalin A; D016572:Cyclosporine; D019703:Calcineurin; D016559:Tacrolimus