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Morphine blood-brain barrier transport is influenced by probenecid co-administration
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (PKPD)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Karlsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (PKPD)
2003 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 20, no 4, 618-623 p.Article in journal (Refereed) Published
Abstract [en]

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.
Keyword [en]
blood-brain barrier, microdialysis, modeling, morphine, probenecid-sensitive transporters
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-72302DOI: 10.1023/A:1023250900462PubMedID: 12739770OAI: oai:DiVA.org:uu-72302DiVA: diva2:100213
Available from: 2005-05-20 Created: 2005-05-20 Last updated: 2017-12-14Bibliographically approved

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