Altered disposition and antinociception of [D-penicillamine(2,5)] enkephalin in mdr1a-gene-deficient mice.

摘要: 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.) administered mdr1a(-/-) and wild-type mice assess systemic disposition antinociception. A subsequent dose-response experiment examined impact of P-gp on DPDPE In addition, time course antinociception determined after a 0.9-mg/kg [mdr1a(-/-) mice] or 24-mg/kg (FVB mice) i.v. dose. Data were fit with series pharmacokinetic-pharmacodynamic models compare action in two mouse strains. 10-mg/kg dose produced >80% maximum possible response at all points mice; peak <20% FVB mice. did not differ between Although brain tissue concentrations 2- 4-fold higher compared mice, required elicit comparable nearly 30-fold lower EC50 differed by an order magnitude Pharmacokinetic-pharmacodynamic modeling indicated difference function distribution within brain, as well blood due differences intrinsic response. The results this suggest is substrate P-gp, responsible, part, for low penetration into brain. substantial absence vs. presence suggests DPDPE-associated sites other than blood-brain interface.