title: Effects of a potent and specific P-glycoprotein inhibitor on the blood-brain barrier distribution and antinociceptive effect of morphine in the rat.
abstract: 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.
authors.affiliation: School of Pharmacy, Division of Drug Delivery and Disposition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7360, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Letrent
authors.forename: G M
authors.initials: GM
authors.lastname: Pollack
authors.forename: K R
authors.initials: KR
authors.lastname: Brouwer
authors.forename: K L
authors.initials: KL
authors.lastname: Brouwer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000166:Acridines / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier; D002540:Cerebral Cortex / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D009020:Morphine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000701:Analgesics, Opioid; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D009020:Morphine; C083501:Elacridar