The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (-/-) and mdr1a (+/+) mice.
1. The aim of this study was to investigate whether blood-brain barrier transport of morphine was affected by the absence of mdr1a-encoded P-glycoprotein (Pgp), by comparing mdr1a (-/-) mice with mdr1a (+/+) mice. 2. Mdr1a (-/-) and (+/+) mice received a constant infusion of morphine for 1, 2 or 4 h (9 nmol/min/mouse). Microdialysis was used to estimate morphine unbound concentrations in brain extracellular fluid during the 4 h infusion. Two methods of estimating in vivo recovery were used: retrodialysis with nalorphine as a calibrator, and the dynamic-no-net-flux method. 3. Retrodialysis loss of morphine and nalorphine was similar in vivo. Unbound brain extracellular fluid concentration ratios of (-/-)/(+/+) were 2.7 for retrodialysis and 3.6 for the dynamic-no-net-flux at 4 h, with corresponding total brain concentration ratios of (-/-)/(+/+) being 2.3 for retrodialysis and 2.6 for the dynamic-no-net-flux. The total concentration ratios of brain/plasma were 1.1 and 0.5 for mdr1a (-/-) and (+/+) mice, respectively. 4. No significant differences in the pharmacokinetics of the metabolite morphine-3-glucoronide were observed between (-/-) and (+/+) mice. 5. In conclusion, comparison between mdr1a (-/-) and (+/+) mice indicates that Pgp participates in regulating the amount of morphine transport across the blood-brain barrier.
Xie
R
R
Division of Biopharmaceutics and Pharmacokinetics, Department of Pharmacy, Faculty of Pharmacy, Uppsala University, Sweden.
Hammarlund-Udenaes
M
M
de Boer
A G
AG
de Lange
E C
EC
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D002540:Cerebral Cortex / Q000098:blood supply*; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D009020:Morphine / Q000097:blood / Q000493:pharmacokinetics*; D009269:Nalorphine / Q000493:pharmacokinetics
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D009020:Morphine; C095122:multidrug resistance protein 3; D009269:Nalorphine