Morphine blood-brain barrier transport is influenced by probenecid co-administration
2003 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 20, no 4, 618-623 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2003. Vol. 20, no 4, 618-623 p.
blood-brain barrier, microdialysis, modeling, morphine, probenecid-sensitive transporters
IdentifiersURN: urn:nbn:se:uu:diva-72302DOI: 10.1023/A:1023250900462PubMedID: 12739770OAI: oai:DiVA.org:uu-72302DiVA: diva2:100213