Enhanced antinociception of the model opioid peptide [D-penicillamine] enkephalin by P-glycoprotein modulation.
Pharm Res
; 16(2): 296-301, 1999 Feb.
Article
em En
| MEDLINE
| ID: mdl-10100317
ABSTRACT
PURPOSE:
This study was conducted to examine the influence of P-glycoprotein (P-gp) modulation on the pharmacodynamics of the model opioid peptide DPDPE.METHODS:
Mice (n = 5-7/group) were pretreated with a single oral dose of the P-gp inhibitor GF120918 (25 or 250 mg/kg) or vehicle. 3H-DPDPE (10 mg/kg) or saline was administered 2.5 hr after pretreatment. Antinociception was determined, and blood and brain tissue were obtained, 10 min after DPDPE administration.RESULTS:
A significant difference (p < 0.001) in DPDPE-associated antinociception was observed among mice pretreated with a 25- (83 +/- 16% MPR) or 250- (95 +/- 5% MPR) mg/kg dose of GF120918 in comparison to mice pretreated with vehicle (24 +/- 14% MPR) or mice receiving GF120918 without DPDPE (12 +/- 8% MPR). A significant difference (p < 0.01) in brain tissue DPDPE concentration also was observed among treatment groups [25 +/- 6 ng/g (vehicle), 37 +/- 11 ng/g (25 mg/kg GF120918), 70 +/- 8 ng/g (250 mg/kg GF120918)]. In contrast, blood DPDPE concentrations were not statistically different between groups (678 +/- 66, 677 +/- 130, and 818 +/- 236 ng/ml for vehicle, GF120918 [25 mg/kg], and GF120918 [250 mg/kg], respectively). A single 100-mg/kg i.p. dose of (+)verapamil increased the brainblood DPDPE concentration ratio by approximately 70% relative to saline-treated control mice (0.139 +/- 0.021 vs. 0.0814 +/- 0.0130, p < 0.01), a change in partitioning similar to that observed with the low dose of GF120918. These data provide further support for a P-gp-based mechanism of brainblood DPDPE distribution.CONCLUSIONS:
The present study demonstrates that GF120918 modulates blood-brain disposition and antinociception of DPDPE. Coadministration of a P-gp inhibitor with DPDPE may improve the pharmacologic activity of this opioid peptide.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Acridinas
/
Medição da Dor
/
Encefalinas
/
Membro 1 da Subfamília B de Cassetes de Ligação de ATP
/
Peptídeos Opioides
/
Tetra-Hidroisoquinolinas
/
Analgésicos
/
Isoquinolinas
Limite:
Animals
Idioma:
En
Revista:
Pharm Res
Ano de publicação:
1999
Tipo de documento:
Article