Pharmaceutical Research

, Volume 20, Issue 4, pp 618–623

Morphine Blood-Brain Barrier Transport Is Influenced by Probenecid Co-Administration

  • Karin Tunblad
  • E. Niclas Jonsson
  • Margareta Hammarlund-Udenaes
Article

DOI: 10.1023/A:1023250900462

Cite this article as:
Tunblad, K., Jonsson, E.N. & Hammarlund-Udenaes, M. Pharm Res (2003) 20: 618. doi:10.1023/A:1023250900462

Abstract

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.

blood-brain barriermicrodialysismodelingmorphineprobenecid-sensitive transporters

Copyright information

© Plenum Publishing Corporation 2003

Authors and Affiliations

  • Karin Tunblad
    • 1
  • E. Niclas Jonsson
    • 1
  • Margareta Hammarlund-Udenaes
    • 1
  1. 1.Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical BiosciencesUppsala UniversityUppsalaSweden