title: Respiratory toxicity of buprenorphine results from the blockage of P-glycoprotein-mediated efflux of norbuprenorphine at the blood-brain barrier in mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  University-affiliated research laboratory, INSERM U705, Paris, France.
  
  
  METHODS
  Wild-type and P-glycoprotein knockout female Friend virus B-type mice.
  
  
  METHODS
  Respiratory effects were studied using plethysmography and the P-glycoprotein role at the blood-brain barrier using in situ brain perfusion.
  
  
  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.
authors.affiliation: INSERM U705, CNRS UMR8206, Université Paris Descartes, Université Paris Diderot, Sorbonne Paris Cité, Faculté de Pharmacie, Neuropsychopharmacologie des addictions, Paris, France.
authors.forename: Hisham
authors.initials: H
authors.lastname: Alhaddad
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cisternino
authors.forename: Xavier
authors.initials: X
authors.lastname: Declèves
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tournier
authors.forename: Joel
authors.initials: J
authors.lastname: Schlatter
authors.forename: Fouad
authors.initials: F
authors.lastname: Chiadmi
authors.forename: Patricia
authors.initials: P
authors.lastname: Risède
authors.forename: Maria
authors.initials: M
authors.lastname: Smirnova
authors.forename: Capucine
authors.initials: C
authors.lastname: Besengez
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
authors.forename: Frédéric J
authors.initials: FJ
authors.lastname: Baud
authors.forename: Bruno
authors.initials: B
authors.lastname: Mégarbane
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D001812:Blood-Brain Barrier; D002047:Buprenorphine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*; D004347:Drug Interactions; D005260:Female; D005602:France; D051379:Mice; D018345:Mice, Knockout; D010991:Plethysmography; D012131:Respiratory Insufficiency / Q000139:chemically induced*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D002047:Buprenorphine; C043585:norbuprenorphine