Impact of Small Molecules Immunosuppressants on P-Glycoprotein Activity and T-cell Function

Authors

  • Inés Llaudó Nephrology Department and Laboratory of Experimental Nephrology, Bellvitge University Hospital, Hospitalet de Llobregat
  • Linda Cassis Nephrology Department and Laboratory of Experimental Nephrology, Bellvitge University Hospital, Hospitalet de Llobregat
  • Joan Torras Nephrology Department and Laboratory of Experimental Nephrology, Bellvitge University Hospital, Hospitalet de Llobregat
  • Oriol Bestard Nephrology Department and Laboratory of Experimental Nephrology, Bellvitge University Hospital, Hospitalet de Llobregat
  • Marcel·la Franquesa Nephrology Department and Laboratory of Experimental Nephrology, Bellvitge University Hospital, Hospitalet de Llobregat
  • Josep M. Cruzado Nephrology Department and Laboratory of Experimental Nephrology, Bellvitge University Hospital, Hospitalet de Llobregat
  • Gema Cerezo Nephrology Department and Laboratory of Experimental Nephrology, Bellvitge University Hospital, Hospitalet de Llobregat
  • Esther Castaño Department of Scientific and Technical Services, University of Barcelona, Hospitalet de Llobregat
  • Jordi Petriz Vall d'Hebron Research Institute, Barcelona
  • Immaculada Herrero-Fresneda Nephrology Department and Laboratory of Experimental Nephrology, Bellvitge University Hospital, Hospitalet de Llobregat
  • Josep M. Grinyó Nephrology Department and Laboratory of Experimental Nephrology, Bellvitge University Hospital, Hospitalet de Llobregat
  • Núria Lloberas Nephrology Department and Laboratory of Experimental Nephrology, Bellvitge University Hospital, Hospitalet de Llobregat

DOI:

https://doi.org/10.18433/J3G30B

Abstract

Purpose. P-glycoprotein (Pgp) is a member of the ABC-transporter family that transports substances across cellular membranes acting as an efflux pump extruding drugs out of the cells. Pgp plays a key role on the pharmacokinetics of several drugs. Herein, we have studied the effects of immunosuppressants on Pgp function, assessing rhodamine-123 (Rho123) uptake and efflux in different T-cell subsets. Methods. Different immunosuppressants such as Cyclosporine (CsA), Rapamycin (Rapa) and Tacrolimus (Tac) were used to assess the in vitro effect on Pgp function of main T-cell subsets among healthy volunteers. We measured Rho123 uptake, efflux and kinetic of extrusion in CD4+ and CD8+ subsets by flow cytometry. Antigen-specific memory T-cell responses were assessed by measuring T-cell proliferation and cytokine secretion using an allogeneic mixed lymphocyte reaction. Results. Rho123 uptake in groups treated with CsA and CsA+Rapa was significantly decreased compared to non-treated group and the other immunosupressants in both T cells subsets. Pgp activity was also reduced in CsA and CsA+Rapa compared to the other immunosupressants but it was only significant in the CsA group for CD8+ subset. Kinetic extrusion of Rho123 by Pgp in all groups was faster in CD8+ T cells. All immunosuppressants and the specific Pgp inhibitor PSC833 diminished antigen-primed T-cell proliferation, especially CD8+ T-cell subset. Conclusions. Our data indicate that small molecules immunosuppressants, especially CsA, inhibit Pgp activity and T-cell function being the CD8+ T cells more susceptible to this effect. These findings support the importance of Pgp when designing combined immunosuppressive regimens. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Published

2012-07-19

How to Cite

Llaudó, I., Cassis, L., Torras, J., Bestard, O., Franquesa, M., Cruzado, J. M., … Lloberas, N. (2012). Impact of Small Molecules Immunosuppressants on P-Glycoprotein Activity and T-cell Function. Journal of Pharmacy & Pharmaceutical Sciences, 15(3), 407–419. https://doi.org/10.18433/J3G30B

Issue

Section

Pharmaceutical Sciences; Review Articles