Blood‐brain barrier transport and brain distribution of morphine‐6‐glucuronide in relation to the antinociceptive effect in rats – pharmacokinetic/pharmacodynamic modelling

• Published in: British journal of pharmacology Vol. 134; no. 8; pp. 1796 - 1804
• Main Authors: Bouw, M René, Xie, Rujia, Tunblad, Karin, Hammarlund‐Udenaes, Margareta
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-12-2001; Nature Publishing
• Subjects: Analgesics; Analgesics, Opioid - blood; Analgesics, Opioid - pharmacokinetics; Analgesics, Opioid - pharmacology; Animals; Antinociceptive effect; Biological and medical sciences; Biological Transport, Active; blood-brain barrier; Blood-Brain Barrier - physiology; Brain - metabolism; effect delay; FARMACI; Half-Life; Male; Medical sciences; Microdialysis; Models, Biological; Morphine Derivatives - blood; Morphine Derivatives - pharmacokinetics; Morphine Derivatives - pharmacology; morphine-6-glucuronide; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; pharmacokinetic-pharmacodynamic modelling; Pharmacology. Drug treatments; PHARMACY; Rats; Rats, Sprague-Dawley; Time Factors; Tissue Distribution; Pharmacokinetic pharmacodynamic relationship; Intravenous administration; Rat; Free form; Rodentia; Central nervous system; Glucuronic acid conjugation; Morphine; Opiates; Narcotic analgesic; Metabolism; Blood brain barrier; Protein; Vertebrata; Biological fixation; Mammalia; Absorption; Animal; Distribution; Drug of abuse; Pharmacokinetics; Brain (vertebrata)
• ISSN: 0007-1188; 1476-5381; 1476-5381
• DOI: 10.1038/sj.bjp.0704406

The objective of this study was to investigate the contribution of the blood‐brain barrier (BBB) transport to the delay in antinociceptive effect of morphine‐6‐glucuronide (M6G), and to study the equilibration of M6G in vivo across the BBB with microdialysis measuring unbound concentrations.
On two consecutive days, rats received an exponential infusion of M6G for 4 h aiming at a target concentration of 3000 ng ml−1 (6.5 μM) in blood. Concentrations of unbound M6G were determined in brain extracellular fluid (ECF) and venous blood using microdialysis and in arterial blood by regular sampling. MD probes were calibrated in vivo using retrodialysis by drug prior to drug administration.
The half‐life of M6G was 23±5 min in arterial blood, 26±10 min in venous blood and 58±17 min in brain ECF (P<0.05; brain vs blood). The BBB equilibration, expressed as the unbound steady‐state concentration ratio, was 0.22±0.09, indicating active efflux in the BBB transport of M6G. A two‐compartment model best described the brain distribution of M6G. The unbound volume of distribution was 0.20±0.02 ml g brain−1. The concentration‐antinociceptive effect relationships exhibited a clear hysteresis, resulting in an effect delay half‐life of 103 min in relation to blood concentrations and a remaining effect delay half‐life of 53 min in relation to brain ECF concentrations.
Half the effect delay of M6G can be explained by transport across the BBB, suggesting that the remaining effect delay of 53 min is a result of drug distribution within the brain tissue or rate‐limiting mechanisms at the receptor level.
British Journal of Pharmacology (2001) 134, 1796–1804; doi:10.1038/sj.bjp.0704406