oa Influence of ABCB1 Gene Polymorphisms and P-Glycoprotein Activity on Cyclosporine Pharmacokinetics in Peripheral Blood Mononuclear Cells in Healthy Volunteers

The calcineurin inhibitor cyclosporine is removed from lymphocytes by the drug efflux transporter Pglycoprotein (P-gp) encoded by the ABCB1 gene for which several single nucleotide polymorphisms (SNPs) have been identified. Of a total of 87 healthy volunteers genotyped for ABCB1 G2677T/A and C3435T SNPs, 10 GG-CC and 9 TTTT individuals were selected and received a single oral dose of cyclosporine. Peripheral blood mononuclear cell (PBMC) ABCB1 mRNA expression, P-gp activity in CD4⁺ and CD8⁺ cells and the 24h cyclosporine pharmacokinetics in PBMCs and whole blood were determined. No correlation was observed between cyclosporine PBMC and whole blood levels (AUC0-24, Spearman, rS=0.09, p=0.71). Intraindividual PBMC and whole blood levels followed parallel profiles that did not significantly differ with respect to tmax(Wilcoxon, p=0.53) and t 1/2(p=0.49). Significant negative correlations between cyclosporine t1/2 in PBMCs and P-gp activity in CD4⁺ (rS=-0.82, p=0.007) and CD8⁺ (rS=-0.72, p=0.03) were observed among TT-TT subjects. Similarly, a negative correlation was detected in the GG-CC group between P-gp activity in CD4⁺ and cyclosporine PBMC AUC0-24(rS=-0.69, p=0.03), as well as PBMC to whole blood AUC0-24 ratio (rS=-0.60, p=0.07). Tested ABCB1 genotypes had no influence on cyclosporine pharmacokinetic parameters in PBMCs and whole blood. The haplotypes investigated were neither significantly correlated with PBMC ABCB1 mRNA expression nor with P-gp activity in CD4⁺ and CD8⁺. In conclusion, cyclosporine PBMC pharmacokinetics was influenced by P-gp activity and cyclosporine whole blood concentrations did not predict PBMC drug levels, suggesting that despite values in the therapeutic range, some subjects could have inadequate intracellular drug levels.