Morphine blood-brain barrier transport is influenced by probenecid co-administration

Purpose. The objective of this study was to investigate the possible influence of probenecid on morphine transport across the blood brain barrier ( BBB) in rats. Methods. Microdialysis probes, calibrated using retrodialysis by drug, were placed into the striatum and jugular vein of seven Sprague Dawley rats. Morphine was administered as a 4- h exponential infusion. The experiment was repeated the next day with the addition of probenecid, administered as a bolus dose ( 20 mg/ kg) followed by a constant infusion ( 20 mg/ kg/ h). Models for BBB transport were built using the computer program NONMEM. Results. The steady- state ratio of 0.29 +/- 0.07 of unbound morphine concentration in brain to that in blood indicates that morphine is actively effluxed at the BBB. Probenecid co- administration increased the ratio to 0.39 +/- 0.04 ( p < 0.05). Models in which probenecid influenced the brain efflux clearance rather than the influx clearance, well described the data. The half- life in brain increased from 58 +/- 9 min to 115 +/- 25 min when probenecid was co- administered. Systemic clearance of morphine also decreased upon probenecid co- administration, and M3G formation was decreased. Conclusion. This study indicates that morphine is a substrate for the probenecid- sensitive transporters at the BBB. Co- administration of probenecid decreased the brain efflux clearance of morphine.