Abstract

This study was undertaken to test the hypothesis that P-glycoprotein (P-gp) modulates opioid peptide pharmacodynamics. [d-Penicillamine^2,5]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 inmdr1a(−/−) 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 betweenmdr1a(−/−) 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.