Combinational inhibition of P-Glycoprotein-mediated etoposide transport by zosuquidar and polysorbate 20

Rasmus Blaaholm Nielsen, René Holm, Ils Pijpers, Jan Snoeys, Ulla Gro Nielsen, Carsten Uhd Nielsen

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P‑glycoprotein (P‑gp) limits the oral absorption of drug substances. Potent small molecule P‑gp inhibitors (e.g., zosuquidar) and nonionic surfactants (e.g., polysorbate 20) inhibit P‑gp by proposedly different mechanisms. Therefore, it was hypothesised that a combination of zosuquidar and polysorbate 20 may potentiate inhibition of P‑gp-mediated efflux. P‑gp inhibition by zosuquidar and polysorbate 20 in combination was assessed in a calcein‑AM assay and in a transcellular etoposide permeability study in MDCKII‑MDR1 and Caco‑2 cells. Furthermore, solutions of etoposide, zosuquidar, and polysorbate 20 were orally administered to Sprague Dawley rats. Zosuquidar elicited a high level of nonspecific adsorption to various labware, which significantly affected the outcomes of the in vitro studies. Still, at certain zosuquidar and polysorbate 20 concentrations, additive P‑gp inhibition was observed in vitro. In vivo, however, oral etoposide bioavailability decreased by coadministration of both zosuquidar and polysorbate 20 when compared to coadministration of etoposide with zosuquidar alone. For future formulation development, the present study provided important and novel knowledge about nonspecific zosuquidar adsorption, as well as insights into combinational P‑gp inhibition by a third-generation P‑gp inhibitor and a P‑gp-inhibiting nonionic surfactant.
Original languageEnglish
Article number283
Issue number1
Publication statusPublished - Jan 2023


  • P-glycoprotein
  • efflux transport
  • etoposide
  • oral absorption
  • polysorbate 20
  • zosuquidar


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