Erschienen in:
01.07.2007 | Original Article
Differential effects of the immunosuppressive agents cyclosporin A, tacrolimus and sirolimus on drug transport by multidrug resistance proteins
verfasst von:
Attaphol Pawarode, Suneet Shukla, Hans Minderman, Stacy M. Fricke, Elaine M. Pinder, Kieran L. O’Loughlin, Suresh V. Ambudkar, Maria R. Baer
Erschienen in:
Cancer Chemotherapy and Pharmacology
|
Ausgabe 2/2007
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Abstract
Purpose
We sought to determine the effects of the immunosuppressants, cyclosporin A (CsA), tacrolimus and sirolimus, on drug transport by the ATP-binding cassette proteins, P-glycoprotein (Pgp; ABCB1), multidrug resistance protein-1 (MRP-1; ABCC1) and breast cancer resistance protein (BCRP; ABCG2), and the major vault protein lung resistance protein (LRP).
Methods
Cellular content of mitoxantrone, a Pgp, MRP-1 and BCRP substrate, was measured by flow cytometry in cells overexpressing these proteins following incubation with and without CsA, tacrolimus or sirolimus. Interaction of BCRP with these compounds was studied by photolabeling and ATPase assays. Nuclear–cytoplasmic distribution of doxorubicin was studied by confocal microscopy in cells overexpressing LRP.
Results
CsA increased cellular drug uptake in cells overexpressing Pgp, MRP-1 or BCRP and nuclear drug uptake in cells overexpressing LRP at the clinically achievable concentration of 2.5 μM. Tacrolimus enhanced cellular drug uptake at 1 μM, but not at 0.08 μM, its clinically achievable concentration, and did not enhance nuclear drug uptake. Sirolimus enhanced cellular drug uptake in cells overexpressing Pgp, MRP-1 and BCRP with optimal effects at 2.5 μM, but was effective at its clinically achievable concentration of 0.25 μM if cells were pre-incubated for at least 30 min before drug exposure, and also enhanced nuclear drug uptake at 0.25 μM. BCRP modulation by all three immunosuppressive agents was associated with competitive binding to the drug transport sites.
Conclusions
CsA, tacrolimus and sirolimus modulate drug transport by Pgp, MRP-1 and BCRP and CsA and sirolimus modulate drug transport by LRP at concentrations that differ from immunosuppressive concentrations and maximum tolerated concentrations.