title: Closer to the Site of Action: Everolimus Concentrations in Peripheral Blood Mononuclear Cells Correlate Well With Whole Blood Concentrations.
abstract: BACKGROUND
  Everolimus (EVE) is an immunosuppressive drug dosed according to therapeutic drug monitoring in renal transplant recipients. The primary site of action is within activated lymphocytes. EVE is a substrate of the efflux transporter ABCB1 also known as P-glycoprotein. Limited data exist regarding a possible association between whole blood and intralymphocyte concentrations of EVE and the potential influence of ABCB1.
  
  
  METHODS
  Twelve renal transplant recipients (5 men and 7 women) treated with EVE underwent a pharmacokinetic investigation where EVE concentrations in whole blood and in peripheral blood mononuclear cells (PBMC) were determined within a dosing interval. In addition, the activity of ABCB1 in PBMC was determined using the Rhodamine123 efflux assay and the patients' genotypes of ABCB1 were determined.
  
  
  RESULTS
  There was a significant correlation between EVE AUC0-12 in whole blood and in PBMC (r = 0.90, P < 0.01), and no association was demonstrated between the ABCB1 activity and EVE PBMC/whole blood ratio of trough concentrations (r = 0.23, P = 0.76). Furthermore, ABCB1 1236C>T, 3435C>T, and 2677G>T/A polymorphism did not influence EVE AUC0-12 PBMC/whole blood ratio.
  
  
  CONCLUSIONS
  The results revealed a significant association between EVE whole blood and PBMC concentrations, suggesting that ABCB1-mediated efflux from PBMC to be of minor importance for the distribution of EVE.
authors.affiliation: *Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo; and Departments of †Pharmacology, and ‡Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Ida
authors.initials: I
authors.lastname: Robertsen
authors.forename: Nils Tore
authors.initials: NT
authors.lastname: Vethe
authors.forename: Karsten
authors.initials: K
authors.lastname: Midtvedt
authors.forename: Pål
authors.initials: P
authors.lastname: Falck
authors.forename: Hege
authors.initials: H
authors.lastname: Christensen
authors.forename: Anders
authors.initials: A
authors.lastname: Åsberg
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016903:Drug Monitoring; D000068338:Everolimus / Q000097:blood*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood*; D007963:Leukocytes, Mononuclear / Q000737:chemistry*; D008297:Male; D008875:Middle Aged
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus