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

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

doi:10.1097/ccm.0b013e318265680a

Cited by 59 publications

(40 citation statements)

References 55 publications

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“…P-gp has been described as a significant determinant of norbuprenorphine brain exposure and antinocicpetion [21]. Efflux of norbuprenorphine via P-gp may be important to prevent respiratory sedation caused by norbuprenorphine [21,24–26]. One recent study has shown that buprenorphine, due to its higher binding affinity and prolonged receptor occupancy, has a protective effect on the respiratory depressive effect of norbuprenorphine [26].…”

Section: Overview Of Drug Dispositionmentioning

confidence: 99%

A review of pharmacological interactions between HIV or hepatitis C virus medications and opioid agonist therapy: implications and management for clinical practice

Bruce

Moody

Altice

et al. 2013

Expert Review of Clinical Pharmacology

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Global access to opioid agonist therapy and HIV/HCV treatment is expanding but when used concurrently, problematic pharmacokinetic and pharmacodynamic interactions may occur. Review of articles from 1966 into 2012 in Medline using the following keywords: HIV, AIDS, HIV therapy, HCV, HCV therapy, antiretroviral therapy, HAART, drug interactions, methadone, and buprenorphine. Additionally, abstracts from national and international meetings and a review of conference proceedings were conducted; selected reports were reviewed as well. The metabolism of both opioid and antiretroviral therapies, description of their known interactions, and clinical implications and management of these interactions are reviewed. Important pharmacokinetic and pharmacodynamic drug interactions affecting either methadone or HIV medications have been demonstrated within each class of antiretroviral agents. Drug interactions between methadone, buprenorphine and HIV medications are known and may have important clinical consequences. Clinicians must be alert to these interactions and have a basic knowledge regarding their management.

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Section: Overview Of Drug Dispositionmentioning

confidence: 99%

A review of pharmacological interactions between HIV or hepatitis C virus medications and opioid agonist therapy: implications and management for clinical practice

Bruce

Moody

Altice

et al. 2013

Expert Review of Clinical Pharmacology

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“…Buprenorphine and its metabolite norbuprenorphine are known to affect P-gp at the BBB. 20 In our previous study, sham and jTBI groups both received buprenorphine and jTBI animals showed a difference in the level of P-gp expression. 4 It is therefore very unlikely that a single injection 6 months before would have any effect on P-gp levels by itself.…”

Section: Juvenile Traumatic Brain Injury Modelmentioning

confidence: 99%

Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

Jullienne

Roberts

Pop

et al. 2014

J Cereb Blood Flow Metab

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In our juvenile traumatic brain injury (jTBI) model, emergence of cognitive dysfunctions was observed up to 6 months after trauma. Here we hypothesize that early brain injury induces changes in the neurovascular unit (NVU) that would be associated with amyloid-beta (Ab) accumulation. We investigated NVU changes for up to 6 months in a rat jTBI model, with a focus on the efflux protein P-glycoprotein (P-gp) and on the basement membrane proteins perlecan and fibronectin, all known to be involved in Ab clearance. Rodent-Ab staining is present and increased after jTBI around cerebral blood microvessels, and the diameter of those is decreased by 25% and 34% at 2 and 6 months, respectively, without significant angiogenesis. P-glycoprotein staining in endothelium is decreased by 22% and parallels an increase of perlecan and fibronectin staining around cerebral blood vessels. Altogether, these results strongly suggest that the emergence of long-term behavioral dysfunctions observed in rodent jTBI may be related to endothelial remodeling at the blood-brain barrier alongside vascular dysfunction and altered Ab trafficking. This study shows that it is important to consider jTBI as a vascular disorder with long-term consequences on cognitive functions.

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“…Administration of the P-gp inhibitor PSC833 in mice was found to significantly increase the respiratory depressive effects of buprenorphine and norbuprenorphine, as well as significantly increase plasma concentrations and reduce brain efflux of norbuprenorphine. Similar effects were also seen in P-gp knock-out mice, suggesting that P-gp plays an important role in the BBB disposition of norbuprenorphine, and that its inhibition can lead to major respiratory side effects (169). A follow up study by the same group found no differences in P-gp mediated BBB transport of buprenorphine or norbuprenoprhine among different strains and genders of mice, despite their variable buprenorphine-induced respiratory toxicities (235).…”

Section: Buprenorphinementioning

confidence: 72%

Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

et al. 2015

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Opioid-related deaths, abuse, and drug interactions are growing epidemic problems that have medical, social, and economic implications. Drug transporters play a major role in the disposition of many drugs, including opioids; hence they can modulate their pharmacokinetics, pharmacodynamics and their associated drug-drug interactions (DDIs). Our understanding of the interaction of transporters with many therapeutic agents is improving; however, investigating such interactions with opioids is progressing relatively slowly despite the alarming number of opioids-mediated DDIs that may be related to transporters. This review presents a comprehensive report of the current literature relating to opioids and their drug transporter interactions. Additionally, it highlights the emergence of transporters that are yet to be fully identified but may play prominent roles in the disposition of opioids, the growing interest in transporter genomics for opioids, and the potential implications of opioid-drug transporter interactions for cancer treatments. A better understanding of drug transporters interactions with opioids will provide greater insight into potential clinical DDIs and could help improve opioids safety and efficacy.

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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

Cited by 59 publications

References 55 publications

A review of pharmacological interactions between HIV or hepatitis C virus medications and opioid agonist therapy: implications and management for clinical practice

A review of pharmacological interactions between HIV or hepatitis C virus medications and opioid agonist therapy: implications and management for clinical practice

Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

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