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


CONCLUSIONS
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.
Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden.
Karin
K
Tunblad
E Niclas
EN
Jonsson
Margareta
M
Hammarlund-Udenaes
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D008297:Male; D017551:Microdialysis; D009020:Morphine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D011339:Probenecid / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009020:Morphine; D011339:Probenecid