Modelling of the blood-brain barrier transport of morphine-3-glucuronide studied using microdialysis in the rat: involvement of probenecid-sensitive transport

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.