Influence of ABCB1 gene polymorphisms and P-glycoprotein activity on cyclosporine pharmacokinetics in peripheral blood mononuclear cells in healthy volunteers.

Détails

ID Serval
serval:BIB_579EC50242B5
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Influence of ABCB1 gene polymorphisms and P-glycoprotein activity on cyclosporine pharmacokinetics in peripheral blood mononuclear cells in healthy volunteers.
Périodique
Drug metabolism letters
Auteur(s)
Ansermot N., Rebsamen M., Chabert J., Fathi M., Gex-Fabry M., Daali Y., Besson M., Rossier M., Rudaz S., Hochstrasser D., Dayer P., Desmeules J.
ISSN
1874-0758 (Electronic)
ISSN-L
1872-3128
Statut éditorial
Publié
Date de publication
04/2008
Peer-reviewed
Oui
Volume
2
Numéro
2
Pages
76-82
Langue
anglais
Notes
Publication types: Controlled Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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.
Mots-clé
ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics, ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism, Administration, Oral, Adult, Area Under Curve, Calcineurin Inhibitors, Cyclosporine/pharmacokinetics, Half-Life, Haplotypes, Humans, Immunosuppressive Agents/pharmacokinetics, Leukocytes, Mononuclear/metabolism, Male, Polymorphism, Single Nucleotide, Tissue Distribution
Pubmed
Création de la notice
21/02/2019 9:22
Dernière modification de la notice
20/08/2019 15:11
Données d'usage