Abstract
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 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.
Footnotes
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Send reprint requests to: Dr. Gary M. Pollack, Division of Drug Delivery and Disposition, School of Pharmacy, Beard Hall CB#7360, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360.
- Abbreviations:
- DPDPE
- [d-penicillamine2,5]enkephalin
- P-gp
- P-glycoprotein
- MPR
- maximum possible response
- mdr1a(−/−)
- mdr1a gene-deficient
- ANOVA
- analysis of variance
- PK-PD
- pharmacokinetic-pharmacodynamic
- Vss
- steady-state volume of distribution
- MRT
- mean residence time
- Cl
- systemic clearance
- CNS
- central nervous system
- Received February 9, 1998.
- Accepted June 15, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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