The role of P-glycoprotein in intestinal transport versus the BBB transport of tetraphenylphosphonium

Avi Swed, Sara Eyal, Igal Madar, Hila Zohar-Kontante, Lola Weiss, Amnon Hoffman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Tetraphenylphosphonium (TPP), a phosphonium cation, is a promising means for tumor imaging. A major contributor to the pharmacokinetics of phosphonium cations is the efflux transporter P-glycoprotein (P-gp). For this application it is important to ascertain the influence of the multidrug resistance system on TPP. Therefore, our aim was to characterize the interaction of TPP with P-gp, in vitro and in in vivo models. P-gpmediated transport of [3H]-TPP was assessed in Caco-2 cells and ex vivo in rat intestinal wall by the use of a diffusion cell system. The distribution of [3H]-TPP across the blood-brain barrier (BBB) was studied in rats and mice treated with P-gp modulators and in Mdr-1a/b(-/-) knockout mice. The in vitro permeability coefficient of basolateral-to-apical transfer (PappB-A) of [ 3H]-TPP was 8-fold greater than apical-to-basolateral (PappA-B) coefficient, indicative of net mucosal secretion. A concentration dependent decrease of this secretion was obtained by the P-gp substrate verapamil, while no effect was evident by the MRP2 inhibitor MK-571 and the BCRP inhibitor FTC. [3H]-TPP transfer across rat jejunum wall was directional and concentration-dependent. 2,4-Dinitrophenol, cyclosporin A (CsA), verapamil and PSC-833 enhanced A-B transport of TPP 3.6-fold, 4-fold, 4.6-fold and 5.3-fold respectively. Likewise, PappA-B of [3H]-TPP was 5-fold greater in P-gp knockout mice than in controls. In vivo, PSC-833, P-gp inhibitor, significantly increased the uptake of [3H]-TPP in the liver, heart, small intestine and the lungs but not the brain. Similar results were obtained in P-gp knockout mice. Our study demonstrates that P-gp mediates TPP efflux in vitro and in vivo; however, the consistently poor BBB permeation of TPP in all in vivo studies including P-gp knockout animals indicates that it is most likely mediated by other mechanisms. These findings are important for optimized clinical application of TPP as an imaging agent in cancer.

Original languageAmerican English
Pages (from-to)1883-1890
Number of pages8
JournalMolecular Pharmaceutics
Issue number6
StatePublished - 7 Dec 2009


  • Absorption
  • BBB uptake
  • Caco-2
  • Dinitrophenol
  • Distribution
  • Imaging
  • Intestinal permeability
  • MDR
  • P-glycoprotein
  • P-gp knockout mice
  • TPP
  • Tumor
  • Ussing chamber
  • Verapamil


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