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Closer to the Site of Action: Everolimus Concentrations in Peripheral Blood Mononuclear Cells Correlate Well With Whole Blood Concentrations

Robertsen, Ida PhD*; Vethe, Nils Tore PhD; Midtvedt, Karsten MD, PhD; Falck, Pål PhD*; Christensen, Hege PhD*; Åsberg, Anders PhD*,‡

doi: 10.1097/FTD.0000000000000185
Short Communication
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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.

*Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo; and

Departments of Pharmacology, and

Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Correspondence: Ida Robertsen, PhD, Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, 0316 Oslo, Norway (e-mail: ida.robertsen@farmasi.uio.no).

The authors declare no conflict of interest.

Received August 21, 2014

Accepted December 23, 2014

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