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 P-glycoprotein (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 TT-TT 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 (AUC(0-24), Spearman, r(S)=0.09, p=0.71). Intraindividual PBMC and whole blood levels followed parallel profiles that did not significantly differ with respect to t(max) (Wilcoxon, p=0.53) and t((1/2)) (p=0.49). Significant negative correlations between cyclosporine t((1/2)) in PBMCs and P-gp activity in CD4(+) (r(S)=-0.82, p=0.007) and CD8(+) (r(S)=-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 AUC(0-24) (r(S)=-0.69, p=0.03), as well as PBMC to whole blood AUC(0-24) ratio (r(S)=-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.
Division of Clinical Pharmacology and Toxicology, University Hospitals of Geneva, Rue Micheli-du-Crest 24, Geneva 14, Switzerland.
Nicolas
N
Ansermot
Michela
M
Rebsamen
Jocelyne
J
Chabert
Marc
M
Fathi
Marianne
M
Gex-Fabry
Youssef
Y
Daali
Marie
M
Besson
Michel
M
Rossier
Serge
S
Rudaz
Denis
D
Hochstrasser
Pierre
P
Dayer
Jules
J
Desmeules
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000493:pharmacokinetics*; D006207:Half-Life; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide; D014018:Tissue Distribution
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine