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Vol. 27, Issue 7, 827-834, July 1999
School of Pharmacy, Division of Drug Delivery and Disposition,
University of North Carolina at Chapel Hill, Chapel Hill, North
Carolina (S.P.L., G.M.P., K.L.R.B.); and Division of Bioanalysis and
Drug Metabolism, Glaxo Wellcome Inc, Research Triangle Park, North
Carolina (K.R.B.)
Previous data suggest that the analgesic effect of morphine may be
modulated by P-glycoprotein (P-gp) inhibition. The effects of the P-gp
inhibitor GF120918 on brain distribution and antinociceptive effects of
morphine were examined in a rat cerebral microdialysis model.
Pretreatment with GF120918 increased both the area under the
concentration-time curve of unbound morphine in brain extracellular fluid (ECF) and morphine-associated antinociception. The area under the
concentration-time curve ratio for unbound morphine in brain ECF
versus unbound morphine in blood was significantly higher in
GF120918-treated rats compared with control rats (1.21 ± 0.34 versus 0.47 ± 0.05, respectively; p < .05).
Modulation of morphine brain-blood distribution was confirmed by
quantitating brain tissue morphine in a separate group of rats;
GF120918 increased the brain tissue:serum concentration ratio
approximately 3-fold. The half-life of unbound morphine in brain ECF
was approximately 3-fold longer in GF120918-treated rats compared with
controls (p < .05). The fraction unbound of
morphine in whole blood was not altered significantly in the presence
of GF120918 (0.651 ± 0.039) as compared with controls (0.662 ± 0.035). Concentrations of unbound morphine-3-glucuronide in blood
and brain ECF were increased in GF120918-treated rats versus controls.
An integrated pharmacokinetic/pharmacodynamic model was developed to
characterize the unbound blood and brain ECF morphine concentration
profiles and concentration-effect relationships. The results of this
study indicate that alteration of morphine antinociception by a potent P-gp inhibitor appears to be mediated at the level of the blood-brain barrier.
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