Respiratory toxicity of buprenorphine results from the blockage of P-glycoprotein-mediated efflux of norbuprenorphine at the blood–brain barrier in mice
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...
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| Veröffentlicht in: | Critical care medicine 2012-12, Vol.40 (12), p.3215-3223 |
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| creator | Alhaddad, Hisham Cisternino, Salvatore Declèves, Xavier Tournier, Nicolas Schlatter, Joel Chiadmi, Fouad Risède, Patricia Smirnova, Maria Besengez, Capucine Scherrmann, Jean-Michel Baud, Frédéric J Mégarbane, Bruno |
| description | 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. |
| doi_str_mv | 10.1097/CCM.0b013e318265680a |
| format | Article |
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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.]]></description><identifier>ISSN: 0090-3493</identifier><identifier>EISSN: 1530-0293</identifier><identifier>DOI: 10.1097/CCM.0b013e318265680a</identifier><identifier>PMID: 22975888</identifier><identifier>CODEN: CCMDC7</identifier><language>eng</language><publisher>Hagerstown, MD: by the Society of Critical Care Medicine and Lippincott Williams & Wilkins</publisher><subject>Analgesics, Opioid - toxicity ; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy ; Animals ; ATP-Binding Cassette, Sub-Family B, Member 1 - physiology ; Biological and medical sciences ; Biological Transport, Active - drug effects ; Blood-Brain Barrier ; Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis ; Buprenorphine - analogs & derivatives ; Buprenorphine - pharmacokinetics ; Buprenorphine - toxicity ; Cardiology and cardiovascular system ; Drug Interactions ; Emerging diseases ; Female ; France ; Human health and pathology ; Infectious diseases ; Intensive care medicine ; Life Sciences ; Medical sciences ; Mice ; Mice, Knockout ; Plethysmography ; Pulmonology and respiratory tract ; Respiratory Insufficiency - chemically induced ; Toxicology ; Transfusions. Complications. Transfusion reactions. Cell and gene therapy</subject><ispartof>Critical care medicine, 2012-12, Vol.40 (12), p.3215-3223</ispartof><rights>2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins</rights><rights>2014 INIST-CNRS</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4414-d88491a8e012aceb204fb96eacf820b46507c8d7312386528d89edd08e13a5313</citedby><cites>FETCH-LOGICAL-c4414-d88491a8e012aceb204fb96eacf820b46507c8d7312386528d89edd08e13a5313</cites><orcidid>0000-0002-2522-2764 ; 0000-0002-9526-2294</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26720517$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22975888$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-03878449$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Alhaddad, Hisham</creatorcontrib><creatorcontrib>Cisternino, Salvatore</creatorcontrib><creatorcontrib>Declèves, Xavier</creatorcontrib><creatorcontrib>Tournier, Nicolas</creatorcontrib><creatorcontrib>Schlatter, Joel</creatorcontrib><creatorcontrib>Chiadmi, Fouad</creatorcontrib><creatorcontrib>Risède, Patricia</creatorcontrib><creatorcontrib>Smirnova, Maria</creatorcontrib><creatorcontrib>Besengez, Capucine</creatorcontrib><creatorcontrib>Scherrmann, Jean-Michel</creatorcontrib><creatorcontrib>Baud, Frédéric J</creatorcontrib><creatorcontrib>Mégarbane, Bruno</creatorcontrib><title>Respiratory toxicity of buprenorphine results from the blockage of P-glycoprotein-mediated efflux of norbuprenorphine at the blood–brain barrier in mice</title><title>Critical care medicine</title><addtitle>Crit Care Med</addtitle><description><![CDATA[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.]]></description><subject>Analgesics, Opioid - toxicity</subject><subject>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</subject><subject>Animals</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - physiology</subject><subject>Biological and medical sciences</subject><subject>Biological Transport, Active - drug effects</subject><subject>Blood-Brain Barrier</subject><subject>Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis</subject><subject>Buprenorphine - analogs & derivatives</subject><subject>Buprenorphine - pharmacokinetics</subject><subject>Buprenorphine - toxicity</subject><subject>Cardiology and cardiovascular system</subject><subject>Drug Interactions</subject><subject>Emerging diseases</subject><subject>Female</subject><subject>France</subject><subject>Human health and pathology</subject><subject>Infectious diseases</subject><subject>Intensive care medicine</subject><subject>Life Sciences</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Plethysmography</subject><subject>Pulmonology and respiratory tract</subject><subject>Respiratory Insufficiency - chemically induced</subject><subject>Toxicology</subject><subject>Transfusions. Complications. Transfusion reactions. Cell and gene therapy</subject><issn>0090-3493</issn><issn>1530-0293</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkctu1DAUhi0EokPhDRDyhkUXaY8vSZxlNYIWaVARgnXkOCeNqSeObKft7PoO3fF4PAmJpheBN77o-39L5yPkPYNjBlV5sl5_PYYGmEDBFC_yQoF-QVYsF5ABr8RLsgKoIBOyEgfkTYy_AJjMS_GaHHBelblSakV-f8c42qCTDzua_K01Nu2o72gzjQEHH8beDkgDxsmlSLvgtzT1SBvnzZW-xAX9ll26nfFj8AntkG2xtTphS7Hr3HS7EHPPv306Pbb49s_dfRO0HWijQ7AY6HzcWoNvyatOu4jvHvZD8vPzpx_r82xzcfZlfbrJjJRMZq1SsmJaITCuDTYcZNdUBWrTKQ6NLHIojWpLwbhQRc5VqypsW1DIhM4FE4fkaN_ba1ePwW512NVe2_r8dFMvbyBUqaSsrhdW7lkTfIwBu6cAg3rRUs9a6v-1zLEP-9g4NfN4nkKPHmbg4wOgo9GuC3owNj5zRckhZ-Xz_zfeJQzxyk03GOoetUt9DfMSXBYZn2fB-HzLYJEu_gKbHqmg</recordid><startdate>201212</startdate><enddate>201212</enddate><creator>Alhaddad, Hisham</creator><creator>Cisternino, Salvatore</creator><creator>Declèves, Xavier</creator><creator>Tournier, Nicolas</creator><creator>Schlatter, Joel</creator><creator>Chiadmi, Fouad</creator><creator>Risède, Patricia</creator><creator>Smirnova, Maria</creator><creator>Besengez, Capucine</creator><creator>Scherrmann, Jean-Michel</creator><creator>Baud, Frédéric J</creator><creator>Mégarbane, Bruno</creator><general>by the Society of Critical Care Medicine and Lippincott Williams & Wilkins</general><general>Lippincott Williams & Wilkins</general><general>Lippincott, Williams & Wilkins</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-2522-2764</orcidid><orcidid>https://orcid.org/0000-0002-9526-2294</orcidid></search><sort><creationdate>201212</creationdate><title>Respiratory toxicity of buprenorphine results from the blockage of P-glycoprotein-mediated efflux of norbuprenorphine at the blood–brain barrier in mice</title><author>Alhaddad, Hisham ; Cisternino, Salvatore ; Declèves, Xavier ; Tournier, Nicolas ; Schlatter, Joel ; Chiadmi, Fouad ; Risède, Patricia ; Smirnova, Maria ; Besengez, Capucine ; Scherrmann, Jean-Michel ; Baud, Frédéric J ; Mégarbane, Bruno</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4414-d88491a8e012aceb204fb96eacf820b46507c8d7312386528d89edd08e13a5313</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Analgesics, Opioid - toxicity</topic><topic>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</topic><topic>Animals</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - physiology</topic><topic>Biological and medical sciences</topic><topic>Biological Transport, Active - drug effects</topic><topic>Blood-Brain Barrier</topic><topic>Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis</topic><topic>Buprenorphine - analogs & derivatives</topic><topic>Buprenorphine - pharmacokinetics</topic><topic>Buprenorphine - toxicity</topic><topic>Cardiology and cardiovascular system</topic><topic>Drug Interactions</topic><topic>Emerging diseases</topic><topic>Female</topic><topic>France</topic><topic>Human health and pathology</topic><topic>Infectious diseases</topic><topic>Intensive care medicine</topic><topic>Life Sciences</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Plethysmography</topic><topic>Pulmonology and respiratory tract</topic><topic>Respiratory Insufficiency - chemically induced</topic><topic>Toxicology</topic><topic>Transfusions. Complications. Transfusion reactions. Cell and gene therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Alhaddad, Hisham</creatorcontrib><creatorcontrib>Cisternino, Salvatore</creatorcontrib><creatorcontrib>Declèves, Xavier</creatorcontrib><creatorcontrib>Tournier, Nicolas</creatorcontrib><creatorcontrib>Schlatter, Joel</creatorcontrib><creatorcontrib>Chiadmi, Fouad</creatorcontrib><creatorcontrib>Risède, Patricia</creatorcontrib><creatorcontrib>Smirnova, Maria</creatorcontrib><creatorcontrib>Besengez, Capucine</creatorcontrib><creatorcontrib>Scherrmann, Jean-Michel</creatorcontrib><creatorcontrib>Baud, Frédéric J</creatorcontrib><creatorcontrib>Mégarbane, Bruno</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Critical care medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Alhaddad, Hisham</au><au>Cisternino, Salvatore</au><au>Declèves, Xavier</au><au>Tournier, Nicolas</au><au>Schlatter, Joel</au><au>Chiadmi, Fouad</au><au>Risède, Patricia</au><au>Smirnova, Maria</au><au>Besengez, Capucine</au><au>Scherrmann, Jean-Michel</au><au>Baud, Frédéric J</au><au>Mégarbane, Bruno</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Respiratory toxicity of buprenorphine results from the blockage of P-glycoprotein-mediated efflux of norbuprenorphine at the blood–brain barrier in mice</atitle><jtitle>Critical care medicine</jtitle><addtitle>Crit Care Med</addtitle><date>2012-12</date><risdate>2012</risdate><volume>40</volume><issue>12</issue><spage>3215</spage><epage>3223</epage><pages>3215-3223</pages><issn>0090-3493</issn><eissn>1530-0293</eissn><coden>CCMDC7</coden><abstract><![CDATA[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.]]></abstract><cop>Hagerstown, MD</cop><pub>by the Society of Critical Care Medicine and Lippincott Williams & Wilkins</pub><pmid>22975888</pmid><doi>10.1097/CCM.0b013e318265680a</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-2522-2764</orcidid><orcidid>https://orcid.org/0000-0002-9526-2294</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0090-3493 |
| ispartof | Critical care medicine, 2012-12, Vol.40 (12), p.3215-3223 |
| issn | 0090-3493 1530-0293 |
| language | eng |
| recordid | cdi_hal_primary_oai_HAL_hal_03878449v1 |
| source | MEDLINE; Journals@Ovid Complete |
| subjects | Analgesics, Opioid - toxicity Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Animals ATP-Binding Cassette, Sub-Family B, Member 1 - physiology Biological and medical sciences Biological Transport, Active - drug effects Blood-Brain Barrier Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis Buprenorphine - analogs & derivatives Buprenorphine - pharmacokinetics Buprenorphine - toxicity Cardiology and cardiovascular system Drug Interactions Emerging diseases Female France Human health and pathology Infectious diseases Intensive care medicine Life Sciences Medical sciences Mice Mice, Knockout Plethysmography Pulmonology and respiratory tract Respiratory Insufficiency - chemically induced Toxicology Transfusions. Complications. Transfusion reactions. Cell and gene therapy |
| title | Respiratory toxicity of buprenorphine results from the blockage of P-glycoprotein-mediated efflux of norbuprenorphine at the blood–brain barrier in mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-30T17%3A15%3A15IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_hal_p&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Respiratory%20toxicity%20of%20buprenorphine%20results%20from%20the%20blockage%20of%20P-glycoprotein-mediated%20efflux%20of%20norbuprenorphine%20at%20the%20blood%E2%80%93brain%20barrier%20in%20mice&rft.jtitle=Critical%20care%20medicine&rft.au=Alhaddad,%20Hisham&rft.date=2012-12&rft.volume=40&rft.issue=12&rft.spage=3215&rft.epage=3223&rft.pages=3215-3223&rft.issn=0090-3493&rft.eissn=1530-0293&rft.coden=CCMDC7&rft_id=info:doi/10.1097/CCM.0b013e318265680a&rft_dat=%3Cpubmed_hal_p%3E22975888%3C/pubmed_hal_p%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/22975888&rfr_iscdi=true |