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Vol. 287, Issue 2, 545-552, November 1998
Division of Drug Delivery and Disposition, School of Pharmacy, The
University of North Carolina at Chapel Hill, Chapel Hill, North
Carolina
This study was undertaken to test the hypothesis that P-glycoprotein
(P-gp) modulates opioid peptide pharmacodynamics.
[D-Penicillamine2,5]enkephalin (DPDPE) (10 mg/kg i.v.) was administered to mdr1a(
/) and wild-type
mice to assess systemic disposition and antinociception. A subsequent
dose-response experiment examined the impact of P-gp on DPDPE
antinociception. In addition, the time course of antinociception was
determined after a 0.9-mg/kg [mdr1a(/) mice] or
24-mg/kg (FVB mice) i.v. dose. Data were fit with a series of
pharmacokinetic-pharmacodynamic models to compare the disposition and
action of DPDPE in the two mouse strains. A 10-mg/kg dose produced
>80% maximum possible response at all time points in
mdr1a(/) mice; peak antinociception was <20% maximum
possible response in FVB mice. DPDPE systemic disposition did not
differ between the two mouse strains. Although brain tissue
concentrations were 2- to 4-fold higher in mdr1a(/) compared to FVB mice, the dose required to elicit comparable
antinociception was nearly 30-fold lower in mdr1a(/)
mice; brain tissue EC50 differed by an order of magnitude
in the two mouse strains. Pharmacokinetic-pharmacodynamic modeling
indicated that the difference in antinociception between mdr1a(/) and FVB mice was a function of DPDPE
distribution within brain, as well as between blood and brain, and not
due to differences in intrinsic response. The results of this study
suggest that DPDPE is a substrate of P-gp, and that P-gp is
responsible, in part, for the low penetration of DPDPE into brain. The
substantial difference in brain tissue EC50 in the absence
vs. presence of P-gp suggests that P-gp modulates DPDPE-associated
antinociception at sites other than the blood-brain interface.
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