Rj. Xie et al., The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (-/-) and mdr1a (+/+)mice, BR J PHARM, 128(3), 1999, pp. 563-568
1 The aim of this study was to investigate whether blood-brain barrier tran
sport of morphine was affected by the absence of mdr1a-encoded P-glycoprote
in (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. Unboun
d brain extracellular fluid concentration ratios of (-/-)/(+/+) were 2.7 fo
r retrodialysis and 3.6 for the dynamic-no-net-flux at 4 h, with correspond
ing total brain concentration ratios of (-/-)/(+/+) being 2.3 for retrodial
ysis 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 morp
hine-3-glucoronide were observed between (-/-) and (+/+) mice.
5 In conclusion, comparison between mdr1a (-/-) and (+/+) mice indicates th
at Pgp participates in regulating the amount of morphine transport across t
he blood-brain barrier.