Whole-blood cultures from renal-transplant patients stimulated ex vivo show that the effects of cyclosporine on lymphocyte proliferation are related to P-glycoprotein expression.
BACKGROUND
Cyclosporine (CsA) is a substrate for the MDR-1 gene product P-glycoprotein (P-gp). CsA efficacy may be modulated by lymphocyte P-gp expression levels. In this study, CsA inhibition of lymphocyte proliferation in whole-blood cultures ex vivo has been related to (1) lymphocyte P-gp expression and (2) the C3435T polymorphism in the MDR-1 gene, which has been reported to alter P-gp function.


METHODS
In 30 renal-transplant recipients taking CsA monotherapy, P-gp expression was measured by flow cytometry. Whole-blood samples were stimulated with purified protein derivative (PPD) and phytohemagglutinin (PHA). CsA resistance ex vivo was defined as less than 10% reduction in proliferation with either PPD or PHA at 2 hours compared with 0 hours.


RESULTS
CsA resistance was associated with greater P-gp expression using either PPD (median expression, resistant 1.89 vs. sensitive 0.96, P =0.02) or PHA (1.66 vs. 0.96, respectively, P =0.02). Whole-blood CsA levels in resistant and sensitive patients were similar. The C3435T polymorphism did not affect inhibition of proliferation by CsA (P >0.05 for all between genotype group comparisons).


CONCLUSIONS
Our results indicate that lymphocyte P-gp expression determines the degree of inhibition of proliferation by CsA ex vivo; whether this also affects CsA effectiveness in vivo and therefore graft survival requires further study.
Singh
Dave
D
Department of Pharmacology and Therapeutics, The University of Liverpool and Royal Liverpool University Hospital, Liverpool, UK. dsingh@meu.org.uk
Alexander
John
J
Owen
Andrew
A
Rustom
Rana
R
Bone
Mike
M
Hammad
Abdel
A
Roberts
Norman
N
Park
Kevin
K
Pirmohamed
Munir
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000008:administration & dosage*; D003596:Cytosine; D004351:Drug Resistance; D005260:Female; D019450:Genes, MDR / Q000235:genetics; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016030:Kidney Transplantation; D008214:Lymphocytes / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010835:Phytohemagglutinins / Q000494:pharmacology*; D011110:Polymorphism, Genetic / Q000235:genetics; D013941:Thymine; D014373:Tuberculin / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D010835:Phytohemagglutinins; D014373:Tuberculin; D016572:Cyclosporine; D003596:Cytosine; D013941:Thymine