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

Abstract

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-gp-mediated 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.

• Authors: Avi Swed, Sara Eyal, Igal Madar, Hila Zohar-Kontante, Lola Weiss, Amnon Hoffman
• Journal: Molecular pharmaceutics (Mol Pharm) 2009 Nov-Dec Vol. 6 Issue 6 Pg. 1883-90 ISSN: 1543-8392 [Electronic] United States
• PMID: 19722701 (Publication Type: Journal Article)

Chemical References

• ABCC2 protein, human
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Abcg2 protein, mouse
• Calcium Channel Blockers
• Cyclosporins
• Enzyme Inhibitors
• Leukotriene Antagonists
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• Onium Compounds
• Organophosphorus Compounds
• Propionates
• Quinolines
• Uncoupling Agents
• verlukast
• Cyclosporine
• Verapamil
• 2,4-Dinitrophenol
• valspodar
• tetraphenylphosphonium

Topics

• 2,4-Dinitrophenol (pharmacology)
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, genetics, metabolism, physiology)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (antagonists & inhibitors, metabolism)
• Animals
• Biological Transport (drug effects)
• Blood-Brain Barrier (metabolism)
• Caco-2 Cells
• Calcium Channel Blockers (pharmacology)
• Cyclosporine (pharmacology)
• Cyclosporins (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Female
• Humans
• In Vitro Techniques
• Intestinal Mucosa (metabolism)
• Leukotriene Antagonists (pharmacology)
• Mice
• Mice, Knockout
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (antagonists & inhibitors, metabolism)
• Onium Compounds (metabolism)
• Organophosphorus Compounds (metabolism)
• Propionates (pharmacology)
• Quinolines (pharmacology)
• Rats
• Uncoupling Agents (pharmacology)
• Verapamil (pharmacology)