title: 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.affiliation: Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Avi
authors.initials: A
authors.lastname: Swed
authors.forename: Sara
authors.initials: S
authors.lastname: Eyal
authors.forename: Igal
authors.initials: I
authors.lastname: Madar
authors.forename: Hila
authors.initials: H
authors.lastname: Zohar-Kontante
authors.forename: Lola
authors.initials: L
authors.lastname: Weiss
authors.forename: Amnon
authors.initials: A
authors.lastname: Hoffman
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism*; D018938:Caco-2 Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D020024:Leukotriene Antagonists / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009861:Onium Compounds / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D014475:Uncoupling Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D019297:2,4-Dinitrophenol; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D002121:Calcium Channel Blockers; D016572:Cyclosporine; D003524:Cyclosporins; D004791:Enzyme Inhibitors; D020024:Leukotriene Antagonists; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009861:Onium Compounds; D009943:Organophosphorus Compounds; D011422:Propionates; D011804:Quinolines; D014475:Uncoupling Agents; D014700:Verapamil; C000715087:ABCC2 protein, human; C501412:Abcg2 protein, mouse; C059141:verlukast; C070272:valspodar; C013289:tetraphenylphosphonium