Abstract | OBJECTIVES: SETTING: University-affiliated research laboratory, INSERM U705, Paris, France. SUBJECTS: Wild-type and P-glycoprotein knockout female Friend virus B-type mice. INTERVENTIONS: Respiratory effects were studied using plethysmography and the P-glycoprotein role at the blood-brain barrier using in situ brain perfusion. MEASUREMENTS AND MAIN RESULTS:
Norbuprenorphine(≥ 1 mg/kg) and to a lesser extent buprenorphine (≥ 10 mg/kg) were responsible for dose-dependent respiratory depression combining increased inspiratory (TI) and expiratory times (TE). PSC833, a powerful P-glycoprotein inhibitor, significantly enhanced buprenorphine-related effects on TI (p < .01) and TE (p < .05) and norbuprenorphine-related effects on minute volume (VE, p < .05), TI, and TE (p < .001). In P-glycoprotein-knockout mice, buprenorphine-related effects on VE (p < .01), TE (p < .001), and TI (p < .05) and norbuprenorphine-related effects on VE (p < .05) and TI (p < .001) were significantly enhanced. Plasma norbuprenorphine concentrations were significantly increased in PSC833-treated mice (p < .001), supporting a P-glycoprotein role in norbuprenorphine pharmacokinetics. Brain norbuprenorphine efflux was significantly reduced in PSC833-treated and P-glycoprotein-knockout mice (p < .001), supporting P-glycoprotein-mediated norbuprenorphine transport at the blood-brain barrier. CONCLUSIONS:
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Authors | Hisham Alhaddad, Salvatore Cisternino, Xavier Declèves, Nicolas Tournier, Joel Schlatter, Fouad Chiadmi, Patricia Risède, Maria Smirnova, Capucine Besengez, Jean-Michel Scherrmann, Frédéric J Baud, Bruno Mégarbane |
Journal | Critical care medicine
(Crit Care Med)
Vol. 40
Issue 12
Pg. 3215-23
(Dec 2012)
ISSN: 1530-0293 [Electronic] United States |
PMID | 22975888
(Publication Type: Journal Article)
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Chemical References |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Analgesics, Opioid
- Buprenorphine
- norbuprenorphine
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Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(physiology)
- Analgesics, Opioid
(toxicity)
- Animals
- Biological Transport, Active
(drug effects)
- Blood-Brain Barrier
- Buprenorphine
(analogs & derivatives, pharmacokinetics, toxicity)
- Drug Interactions
- Female
- France
- Mice
- Mice, Knockout
- Plethysmography
- Respiratory Insufficiency
(chemically induced)
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