Modelling of the blood-brain barrier transport of morphine-3-glucuronide studied using microdialysis in the rat: involvement of probenecid-sensitive transport
Rj. Xie et al., Modelling of the blood-brain barrier transport of morphine-3-glucuronide studied using microdialysis in the rat: involvement of probenecid-sensitive transport, BR J PHARM, 131(8), 2000, pp. 1784-1792
1 The objective of this study was to investigate the impact of probenecid o
n the blood-brain barrier (BBB) transport of morphine-3-glucuronide (M3G).
2 Two groups of rats received an exponential infusion of M3G over 4 h to re
ach a target plasma concentration of 65 muM on two consecutive days. Proben
ecid was co-administered in the treatment group on day 2. Microdialysis was
used to estimate unbound M3G concentrations in brain extracellular fluid (
ECF) and blood. In vivo recovery of M3G was calculated with retrodialysis b
y drug, preceding the drug administration. The BBB transport was modelled u
sing NONMEM.
3 In the probenecid group, the ratio of the steady-state concentration of u
nbound M3G in brain ECF to that in blood was 0.08+/-0.02 in the absence and
0.16+/-0.05 in the presence of probenecid (P = 0.001). In the control grou
p, no significant difference was found in this ratio between the 2 days (0.
11+/-0.05 and 0.10+/-0.02, respectively). The process that appears to be ma
inly influenced by probenecid is influx clearance into the brain (0.11 mul
min(-1) g-brain(-1) vs 0.17 mul min(-1) g-brain(-1), in the absence vs pres
ence of probenecid, P<0.001). The efflux clearance was 1.15 <mu>l min(-1) g
-brain(-1). The half-life of M3G was 81+/-25 min in brain ECF vs 22+/-2 mil
l in blood (P<0.0001). Blood pharmacokinetics was not influenced by probene
cid.
4 In conclusion, a probenecid-sensitive transport system is involved in the
transport of M3G across the BBB.