Exploiting Transport Activity of P-Glycoprotein at the Blood–Brain Barrier for the Development of Peripheral Cannabinoid Type 1 Receptor Antagonists

• Published in: Molecular pharmaceutics 2012-05, Vol.9 (5), p.1351-1360
• Main Authors: Wittgen, Hanneke G. M, Greupink, Rick, van den Heuvel, Jeroen J. M. W, van den Broek, Petra H. H, Dinter-Heidorn, Heike, Koenderink, Jan B, Russel, Frans G. M
• Format: Article
• Language: English
• Subjects: Acridines - pharmacology; Animals; ATP Binding Cassette Transporter, Sub-Family B; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological Transport - drug effects; Blood-Brain Barrier; Blotting, Western; Cannabinoid Receptor Antagonists - metabolism; Cannabinoid Receptor Antagonists - pharmacology; Cell Line; Humans; Kinetics; Male; Neoplasm Proteins - metabolism; Piperidines - pharmacology; Pyrazoles - pharmacology; Quinidine - pharmacology; Rats; Rats, Wistar; Tandem Mass Spectrometry; Tetrahydroisoquinolines - pharmacology
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/mp200617z

Although the CB1 receptor antagonist/inverse agonist rimonabant has positive effects on weight loss and cardiometabolic risk factors, neuropsychiatric side effects have prompted researchers to develop peripherally acting derivatives. Here, we investigated for a series of 3,4-diarylpyrazoline CB1 receptor antagonists if transport by the brain efflux transporter P-gp could be used as a selection criterion in the development of such drugs. All 3,4-diarylpyrazolines and rimonabant inhibited P-gp transport activity in membrane vesicles isolated from HEK293 cells overexpressing the transporter, but only the 1,1-dioxo-thiomorpholino analogue 23 exhibited a reduced accumulation (−38 ± 2%) in these cells, which could be completely reversed by the P-gp/BCRP inhibitor elacridar. In addition, 23 appeared to be a BCRP substrate, whereas rimonabant was not. In rats, the in vivo brain/plasma concentration ratio of 23 was significantly lower than for rimonabant (0.4 ± 0.1 vs 6.2 ± 1.6, p < 0.001). Coadministration of elacridar resulted in an 11-fold increase of the brain/plasma ratio for 23 (p < 0.01) and only 1.4-fold for rimonabant (p < 0.05), confirming the involvement of P-gp and possibly BCRP in limiting the brain entrance of 23 in vivo. In conclusion, these data support the conception that efflux via transporters such as P-gp and BCRP can limit the brain penetration of CB1 receptor antagonists, and that this property could be used in the development of peripheral antagonists.