The role of P‐glycoprotein in blood‐brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (−/−) and mdr1a (+/+) mice

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. 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. 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. No significant differences in the pharmacokinetics of the metabolite morphine‐3‐glucoronide were observed between (−/−) and (+/+) mice. In conclusion, comparison between mdr1a (−/−) and (+/+) mice indicates that Pgp participates in regulating the amount of morphine transport across the blood‐brain barrier. British Journal of Pharmacology (1999) 128, 563–568; doi:10.1038/sj.bjp.0702804