Differential effects of the immunosuppressive agents cyclosporin A, tacrolimus and sirolimus on drug transport by multidrug resistance proteins

Cancer Chemother Pharmacol. 2007 Jul;60(2):179-88. doi: 10.1007/s00280-006-0357-8. Epub 2006 Oct 10.


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 microM. Tacrolimus enhanced cellular drug uptake at 1 microM, but not at 0.08 microM, 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 microM, but was effective at its clinically achievable concentration of 0.25 microM if cells were pre-incubated for at least 30 min before drug exposure, and also enhanced nuclear drug uptake at 0.25 microM. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism*
  • Biological Transport
  • Cell Nucleus / metabolism
  • Cyclosporine / pharmacokinetics*
  • Dose-Response Relationship, Drug
  • Drug Resistance, Multiple*
  • HL-60 Cells / drug effects
  • HL-60 Cells / metabolism
  • Humans
  • Immunosuppressive Agents / pharmacokinetics*
  • Sirolimus / pharmacokinetics*
  • Tacrolimus / pharmacokinetics*


  • ATP-Binding Cassette Transporters
  • Immunosuppressive Agents
  • Cyclosporine
  • Sirolimus
  • Tacrolimus