Influence of probenecid on the delivery of morphine-6-glucuronide to the brain

The objective was to evaluate the influence of probenecid on the blood-brain barrier (BBB) transport of morphine-6-glucuronide (M6G). Microdialysis probes were placed in the striatum and into the jugular vein of Sprague-Dawley rats. Each probe was calibrated in vivo using retrodialysis by drug. M6G was administered as a 4-h exponential i.v. infusion, and the experiment was repeated the following day with the addition of probenecid. The data were analysed using NONMEM. An integrated model including the total arterial concentrations, the dialysate concentrations in brain and blood, and the recovery measurements, was developed. The extent of BBB transport, expressed as the ratio between clearance into the brain and clearance out of the brain (CLin/CLout), was estimated as 0.29 on both days, indicating that efflux transporters act on M6G at the BBB. However, the probenecid-sensitive transporters are not involved in the brain efflux, as the ratio was unaltered although probenecid was co-administered. In contrast, the systemic elimination of M6G decreased by 22% (p < 0.05) upon probenecid co-administration. The half-life of M6G was longer in the brain than in blood on both experimental days (p < 0.05). In conclusion, probenecid decreased the systemic elimination of M6G, but had no effect on the BBB transport of M6G. (C) 2004 Elsevier B.V. All rights reserved.