Exploiting Transport Activity of P-Glycoprotein at the Blood鈥揃rain Barrier for the Development of Peripheral Cannabinoid Type 1 Receptor Antagonists
详细信息 查看全文
- 作者：Hanneke G. M. Wittgen ; Rick Greupink ; Jeroen J. M. W. van den Heuvel ; Petra H. H. van den Broek ; Heike Dinter-Heidorn ; Jan B. Koenderink ; Frans G. M. Russel
- 刊名：Molecular Pharmaceutics
- 出版年：2012
- 出版时间：May 7, 2012
- 年：2012
- 卷：9
- 期：5
- 页码：1351-1360
- 全文大小：345K
- 年卷期：v.9,no.5(May 7, 2012)
- ISSN：1543-8392
文摘
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 (鈭?8 卤 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 卤 0.1 vs 6.2 卤 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 23in 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.