Enhanced antinociception of the model opioid peptide [D-penicillamine] enkephalin by P-glycoprotein modulation.
OBJECTIVE
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 brain:blood 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 brain:blood 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.
Chen
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Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina at Chapel Hill 27599-7360, USA.
Pollack
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000166:Acridines / Q000494:pharmacology*; D000700:Analgesics / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004333:Drug Administration Routes; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D018847:Opioid Peptides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects*; D044005:Tetrahydroisoquinolines; D014018:Tissue Distribution; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000700:Analgesics; D004745:Enkephalins; D007546:Isoquinolines; D018847:Opioid Peptides; D044005:Tetrahydroisoquinolines; D020881:Enkephalin, D-Penicillamine (2,5)-; D014700:Verapamil; C083501:Elacridar