Exploiting transport activity of p-glycoprotein at the blood-brain barrier for the development of peripheral cannabinoid type 1 receptor antagonists.

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Publication year
2012Source
Molecular Pharmaceutics, 9, 5, (2012), pp. 1351-1360ISSN
Publication type
Article / Letter to editor

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Organization
Pharmacology-Toxicology
IMM - Institute for Molecules and Materials
Journal title
Molecular Pharmaceutics
Volume
vol. 9
Issue
iss. 5
Page start
p. 1351
Page end
p. 1360
Subject
NCEBP 14: Cardiovascular diseases; NCMLS 5: Membrane transport and intracellular motility IGMD 9: Renal disorder; NCMLS 5: Membrane transport and intracellular motility N4i 3: Poverty-related infectious diseasesAbstract
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.
This item appears in the following Collection(s)
- Academic publications [204024]
- Electronic publications [102375]
- Faculty of Medical Sciences [80459]
- Faculty of Science [32153]
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