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The role of P‐glycoprotein in blood‐brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (−/−) and mdr1a (+/+) mice
Author(s) -
Xie Rujia,
HammarlundUdenaes Margareta,
De Boer Albertus G,
De Lange Elizabeth C M
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702804
Subject(s) - microdialysis , chemistry , morphine , nalorphine , p glycoprotein , pharmacology , blood–brain barrier , in vivo , extracellular fluid , pharmacokinetics , metabolite , extracellular , endocrinology , central nervous system , opioid , (+) naloxone , biochemistry , medicine , biology , receptor , microbiology and biotechnology , multiple drug resistance , antibiotics
The aim of this study was to investigate whether blood‐brain barrier transport of morphine was affected by the absence of mdr1a ‐encoded P‐glycoprotein (Pgp), by comparing mdr1a (−/−) mice with mdr1a (+/+) mice.Mdr1a (−/−) and (+/+) mice received a constant infusion of morphine for 1, 2 or 4 h (9 nmol/min/mouse). Microdialysis was used to estimate morphine unbound concentrations in brain extracellular fluid during the 4 h infusion. Two methods of estimating in vivo recovery were used: retrodialysis with nalorphine as a calibrator, and the dynamic‐no‐net‐flux method. Retrodialysis loss of morphine and nalorphine was similar in vivo . Unbound brain extracellular fluid concentration ratios of (−/−)/(+/+) were 2.7 for retrodialysis and 3.6 for the dynamic‐no‐net‐flux at 4 h, with corresponding total brain concentration ratios of (−/−)/(+/+) being 2.3 for retrodialysis and 2.6 for the dynamic‐no‐net‐flux. The total concentration ratios of brain/plasma were 1.1 and 0.5 for mdr1a (−/−) and (+/+) mice, respectively. No significant differences in the pharmacokinetics of the metabolite morphine‐3‐glucoronide were observed between (−/−) and (+/+) mice. In conclusion, comparison between mdr1a (−/−) and (+/+) mice indicates that Pgp participates in regulating the amount of morphine transport across the blood‐brain barrier.British Journal of Pharmacology (1999) 128 , 563–568; doi: 10.1038/sj.bjp.0702804