Effects of a potent and specific P-glycoprotein inhibitor on the blood-brain barrier distribution and antinociceptive effect of morphine in the rat

Previous data suggest that the analgesic effect of morphine may be modulate d by P-glycoprotein (P-gp) inhibition. The effects of the P-gp inhibitor GF 120918 on brain distribution and antinociceptive effects of morphine were e xamined in a rat cerebral microdialysis model. Pretreatment with GF120918 i ncreased both the area under the concentration-time curve of unbound morphi ne in brain extracellular fluid (ECF) and morphine-associated antinocicepti on. The area under the concentration-time curve ratio for unbound morphine in brain ECF versus unbound morphine in blood was significantly higher in G F120918-treated rats compared with control rats (1.21 +/- 0.34 versus 0.47 +/- 0.05, respectively; p <.05). Modulation of morphine brain-blood distrib ution was confirmed by quantitating brain tissue morphine in a separate gro up of rats; GF120918 increased the brain tissue:serum concentration ratio a pproximately 3-fold. The half-life of unbound morphine in brain ECF was app roximately 3-fold longer in GF120918-treated rats compared with controls (p <.05). The fraction unbound of morphine in whole blood was not altered sig nificantly in the presence of GF120918 (0.651 +/- 0.039) as compared with c ontrols (0.662 +/- 0.035). Concentrations of unbound morphine-3-glucuronide in blood and brain ECF were increased in GF120918-treated rats versus cont rols. An integrated pharmacokinetic/pharmacodynamic model was developed to characterize the unbound blood and brain ECF morphine concentration profile s and concentration-effect relationships. The results of this study indicat e that alteration of morphine antinociception by a potent P-gp inhibitor ap pears to be mediated at the level of the blood-brain barrier.