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Respiratory toxicity of buprenorphine results from the blockage of P-glycoprotein-mediated efflux of norbuprenorphine at the blood–brain barrier in mice

Alhaddad, Hisham PharmD, PhD; Cisternino, Salvatore PharmD, PhD; Declèves, Xavier PharmD, PhD; Tournier, Nicolas PharmD, PhD; Schlatter, Joel PharmD; Chiadmi, Fouad PharmD; Risède, Patricia; Smirnova, Maria; Besengez, Capucine; Scherrmann, Jean-Michel PharmD, PhD; Baud, Frédéric J. MD; Mégarbane, Bruno MD, PhD

doi: 10.1097/CCM.0b013e318265680a
Laboratory Investigations

Objectives: Deaths due to asphyxia as well as following acute poisoning with severe respiratory depression have been attributed to buprenorphine in opioid abusers. However, in human and animal studies, buprenorphine exhibited ceiling respiratory effects, whereas its metabolite, norbuprenorphine, was assessed as being a potent respiratory depressor in rodents. Recently, norbuprenorphine, in contrast to buprenorphine, was shown in vitro to be a substrate of human P-glycoprotein, a drug-transporter involved in all steps of pharmacokinetics including transport at the blood–brain barrier. Our objectives were to assess P-glycoprotein involvement in norbuprenorphine transport in vivo and study its role in the modulation of buprenorphine-related respiratory effects in mice.

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: P-glycoprotein plays a key-protective role in buprenorphine-related respiratory effects, by allowing norbuprenorphine efflux at the blood–brain barrier. Our findings suggest a major role for drug–drug interactions that lead to P-glycoprotein inhibition in buprenorphine-associated fatalities and respiratory depression.

From INSERM U705, CNRS UMR8206 (HA, SC, XD, PR, MS, CB, JMS, FJB, BM), Université Paris Descartes, Université Paris Diderot, Sorbonne Paris Cité, Faculté de Pharmacie, Neuropsychopharmacologie des addictions, Paris, France; Réanimation Médicale et Toxicologique (FJB, BM), Assistance Publique–Hôpitaux de Paris, Hôpital Lariboisière, Paris, France; Laboratoire de Toxicologie, Bondy (JS, FS), Assistance Publique–Hôpitaux de Paris, Hôpital Jean Verdier, Bondy, France; and CEA (NT), I2BM, Service hospitalier Frédéric Joliot, Orsay, France.

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None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this article.

The authors have not disclosed any potential conflicts of interest.

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© 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins