1. 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.
- Author
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Singh D, Alexander J, Owen A, Rustom R, Bone M, Hammad A, Roberts N, Park K, and Pirmohamed M
- Subjects
- Administration, Oral, Adult, Aged, Cell Division drug effects, Cells, Cultured, Cytosine, Drug Resistance, Female, Genes, MDR genetics, Genotype, Heterozygote, Homozygote, Humans, Male, Middle Aged, Polymorphism, Genetic genetics, Thymine, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Cyclosporine administration & dosage, Immunosuppressive Agents administration & dosage, Kidney Transplantation, Lymphocytes pathology, Phytohemagglutinins pharmacology, Tuberculin pharmacology
- Abstract
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.
- Published
- 2004
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