Document Detail

Influence of ABCB1 gene polymorphisms and P-glycoprotein activity on cyclosporine pharmacokinetics in peripheral blood mononuclear cells in healthy volunteers.
MedLine Citation:
PMID:  19356075     Owner:  NLM     Status:  MEDLINE    
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.
Nicolas Ansermot; Michela Rebsamen; Jocelyne Chabert; Marc Fathi; Marianne Gex-Fabry; Youssef Daali; Marie Besson; Michel Rossier; Serge Rudaz; Denis Hochstrasser; Pierre Dayer; Jules Desmeules
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Publication Detail:
Type:  Controlled Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Drug metabolism letters     Volume:  2     ISSN:  1872-3128     ISO Abbreviation:  Drug Metab Lett     Publication Date:  2008 Apr 
Date Detail:
Created Date:  2009-04-09     Completed Date:  2009-04-27     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101313587     Medline TA:  Drug Metab Lett     Country:  United Arab Emirates    
Other Details:
Languages:  eng     Pagination:  76-82     Citation Subset:  IM    
Division of Clinical Pharmacology and Toxicology, University Hospitals of Geneva, Rue Micheli-du-Crest 24, Geneva 14, Switzerland.
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MeSH Terms
Administration, Oral
Area Under Curve
Calcineurin / antagonists & inhibitors
Cyclosporine / pharmacokinetics*
Immunosuppressive Agents / pharmacokinetics*
Leukocytes, Mononuclear / metabolism
P-Glycoprotein / genetics,  metabolism*
Polymorphism, Single Nucleotide
Tissue Distribution
Reg. No./Substance:
0/ABCB1 protein, human; 0/Immunosuppressive Agents; 0/P-Glycoprotein; 59865-13-3/Cyclosporine; EC

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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