Inproceedings: An article in a conference proceedings.
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Influence of MDR1 genetic polymorphisms on intralymphocyte concentrations of cyclosporine A in transplant recipients
Cyclosporine A (CsA) presents a wide interindividual variability in its kinetics. CsA is a substrate of P-glycoprotein (PGP), an efflux transporter which is the product of the MDR1 gene and present on intestinal cells, among others. Contradictory reports were published on the influence of MDR1 polymorphisms on CsA blood concentrations. As PGP is also present on lymphocytes, it is likely to influence CsA intracellular concentrations. However, no studies have yet examined the possible effect of MDR1 polymorphisms on the intralymphocyte concentrations of CsA. Whole blood and mononuclear cell samples were collected from 67 Caucasian, renal, liver or lung transplant recipients. CsA intracellular and blood trough concentrations were measured by HPLC-MS. MDR1 genotypes were determined by TaqMan. Log-transformed data from genotype groups were compared by t-test. Blood and intracellular CsA concentrations displayed very wide variation (33-205ng/ml; 0.3-26ng/106 cells). Intracellular CsA concentrations correlated with blood concentrations (r2=32%; p<0.00005) and to a lesser extend with CsA daily dose/kg (r2=14%; p=0.002). Blood concentrations correlated weakly with CsA daily dose/kg (r2=15%; p=0.001). MDR1 3435 CT/TT genotypes had 1.3-fold higher trough CsA blood concentrations than MDR1 3435 CC (CI95%=1.0-1.5; p=0.02). This difference lost its significance when CsA blood concentrations were corrected by CsA daily dose/kg. However, trough CsA intracellular concentrations were 1.9-fold higher in 3435 CT/TT than in CC genotypes (CI95%=1.2-3.0; p=0.006) and this remained significant after correction by CsA daily dose/kg. Intracellular to blood CsA concentration ratios were 1.5-fold higher in 3435 CT/TT than in CC genotypes (CI95%=1.0-2.2; p=0.04). Polymorphisms A61G and G2677T had no influence on CsA blood or intracellular concentrations. In conclusion, the MDR1 3435 CT/TT genotype was associated with CsA poor transporter phenotype, with a stronger impact on intracellular than blood concentrations. The analysis of intracellular CsA concentrations provides new insights in the mechanism of action of calcineurin inhibition and may have therapeutic implications.
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