title: Cannabinoid type 1 receptor antagonists modulate transport activity of multidrug resistance-associated proteins MRP1, MRP2, MRP3, and MRP4.
abstract: Cannabinoid type 1 (CB1) receptor antagonists have been developed for the treatment of obesity, but a major disadvantage is that they cause unwanted psychiatric effects. Selective targeting of peripheral CB1 receptors might be an option to circumvent these side effects. Multidrug resistance-associated proteins (MRPs) can influence the pharmacokinetics of drugs and thereby affect their disposition in the body. In this study, we investigated the interaction of the prototypic CB1 receptor antagonist rimonabant and a series of 3,4-diarylpyrazoline CB1 receptor antagonists with MRP1, MRP2, MRP3, and MRP4 in vitro. Their effect on ATP-dependent transport of estradiol 17-β-D-glucuronide (E(2)17βG) was measured in inside-out membrane vesicles isolated from transporter-overexpressing human embryonic kidney 293 cells. Rimonabant inhibited MRP1 transport activity more potently than MRP4 (K(i) of 1.4 and 4 μM, respectively), whereas the 3,4-diarylpyrazolines were stronger inhibitors of MRP4- than MRP1-mediated transport. A number of CB1 receptor antagonists, including rimonabant, stimulated MRP2 and MRP3 transport activity at low substrate concentrations but inhibited E(2)17βG transport at high substrate concentrations. The interaction of 3,4-diarylpyrazolines and rimonabant with MRP1-4 indicates their potential for drug-drug interactions. Preliminary in vivo data suggested that for some 3,4-diarylpyrazolines the relatively lower brain efficacy may be related to their inhibitory potency against MRP4 activity. Furthermore, this study shows that the modulatory effects of the 3,4-diarylpyrazolines were influenced by their chemical properties and that small variations in structure can determine the affinity of these compounds for efflux transporters and thereby affect their pharmacokinetic behavior.
authors.affiliation: Department of Pharmacology and Toxicology (149), Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Hanneke G M
authors.initials: HG
authors.lastname: Wittgen
authors.forename: Jeroen J M W
authors.initials: JJ
authors.lastname: van den Heuvel
authors.forename: Petra H H
authors.initials: PH
authors.lastname: van den Broek
authors.forename: Heike
authors.initials: H
authors.lastname: Dinter-Heidorn
authors.forename: Jan B
authors.initials: JB
authors.lastname: Koenderink
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D002853:Chromatography, Liquid; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D021381:Protein Transport; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D053719:Tandem Mass Spectrometry
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; D043884:Receptor, Cannabinoid, CB1