CYP2B6 and Bupropion's Smoking-Cessation Pharmacology: The Role of Hydroxybupropion
Bupropion is indicated to promote smoking cessation. Animal studies suggest that the pharmacologic activity of bupropion can be mediated by its major metabolite, hydroxybupropion. We measured plasma bupropion and its metabolite levels in a double‐blind, placebo controlled, randomized smoking‐cessati...
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| Veröffentlicht in: | Clinical pharmacology and therapeutics 2012-12, Vol.92 (6), p.771-777 |
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| creator | Zhu, A Z X Cox, L S Nollen, N Faseru, B Okuyemi, K S Ahluwalia, J S Benowitz, N L Tyndale, R F |
| description | Bupropion is indicated to promote smoking cessation. Animal studies suggest that the pharmacologic activity of bupropion can be mediated by its major metabolite, hydroxybupropion. We measured plasma bupropion and its metabolite levels in a double‐blind, placebo controlled, randomized smoking‐cessation trial. Among the treatment‐adherent individuals, higher hydroxybupropion concentrations (per μg/ml) resulted in better smoking‐cessation outcomes (week 3, 7, and 26 odds ratio (OR) = 2.82, 2.96, and 2.37, respectively, P = 0.005–0.040); this was not observed with bupropion levels (OR = 1.00–1.03, P = 0.59–0.90). Genetic variation in CYP2B6, the enzyme that metabolizes bupropion to hydroxybupropion, was identified as a significant source of variability in hydroxybupropion formation. Our data indicate that hydroxybupropion contributes to the pharmacologic effects of bupropion for smoking cessation, and that variability in response to bupropion treatment is related to variability in CYP2B6‐mediated hydroxybupropion formation. These findings suggest that dosing of bupropion to achieve a hydroxybupropion level of 0.7 μg/ml or increasing bupropion dose for CYP2B6 slow metabolizers could improve bupropion's cessation outcomes.
Clinical Pharmacology & Therapeutics (2012); 92 6, 771–777. doi:10.1038/clpt.2012.186 |
| doi_str_mv | 10.1038/clpt.2012.186 |
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Clinical Pharmacology & Therapeutics (2012); 92 6, 771–777. doi:10.1038/clpt.2012.186</description><identifier>ISSN: 0009-9236</identifier><identifier>EISSN: 1532-6535</identifier><identifier>DOI: 10.1038/clpt.2012.186</identifier><identifier>PMID: 23149928</identifier><identifier>CODEN: CLPTAT</identifier><language>eng</language><publisher>Basingstoke: Blackwell Publishing Ltd</publisher><subject>African Americans ; Antidepressive Agents, Second-Generation - metabolism ; Antidepressive Agents, Second-Generation - therapeutic use ; Aryl Hydrocarbon Hydroxylases - metabolism ; Biological and medical sciences ; Bupropion - analogs & derivatives ; Bupropion - metabolism ; Bupropion - therapeutic use ; Cytochrome P-450 CYP2B6 ; Double-Blind Method ; Humans ; Kinetics ; Logistic Models ; Medical sciences ; Odds Ratio ; Oxidoreductases, N-Demethylating - metabolism ; Pharmacology. Drug treatments ; Predictive Value of Tests ; Smoking - drug therapy ; Smoking Cessation ; Treatment Outcome</subject><ispartof>Clinical pharmacology and therapeutics, 2012-12, Vol.92 (6), p.771-777</ispartof><rights>2012 American Society for Clinical Pharmacology and Therapeutics</rights><rights>2014 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5386-b0688e1ec4ce1048cb7806e5960e1527f69c9170ddf95cfdf1e19026864637613</citedby><cites>FETCH-LOGICAL-c5386-b0688e1ec4ce1048cb7806e5960e1527f69c9170ddf95cfdf1e19026864637613</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1038%2Fclpt.2012.186$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1038%2Fclpt.2012.186$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26756566$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23149928$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhu, A Z X</creatorcontrib><creatorcontrib>Cox, L S</creatorcontrib><creatorcontrib>Nollen, N</creatorcontrib><creatorcontrib>Faseru, B</creatorcontrib><creatorcontrib>Okuyemi, K S</creatorcontrib><creatorcontrib>Ahluwalia, J S</creatorcontrib><creatorcontrib>Benowitz, N L</creatorcontrib><creatorcontrib>Tyndale, R F</creatorcontrib><title>CYP2B6 and Bupropion's Smoking-Cessation Pharmacology: The Role of Hydroxybupropion</title><title>Clinical pharmacology and therapeutics</title><addtitle>Clinical Pharmacology & Therapeutics</addtitle><description>Bupropion is indicated to promote smoking cessation. Animal studies suggest that the pharmacologic activity of bupropion can be mediated by its major metabolite, hydroxybupropion. We measured plasma bupropion and its metabolite levels in a double‐blind, placebo controlled, randomized smoking‐cessation trial. Among the treatment‐adherent individuals, higher hydroxybupropion concentrations (per μg/ml) resulted in better smoking‐cessation outcomes (week 3, 7, and 26 odds ratio (OR) = 2.82, 2.96, and 2.37, respectively, P = 0.005–0.040); this was not observed with bupropion levels (OR = 1.00–1.03, P = 0.59–0.90). Genetic variation in CYP2B6, the enzyme that metabolizes bupropion to hydroxybupropion, was identified as a significant source of variability in hydroxybupropion formation. Our data indicate that hydroxybupropion contributes to the pharmacologic effects of bupropion for smoking cessation, and that variability in response to bupropion treatment is related to variability in CYP2B6‐mediated hydroxybupropion formation. These findings suggest that dosing of bupropion to achieve a hydroxybupropion level of 0.7 μg/ml or increasing bupropion dose for CYP2B6 slow metabolizers could improve bupropion's cessation outcomes.
Clinical Pharmacology & Therapeutics (2012); 92 6, 771–777. doi:10.1038/clpt.2012.186</description><subject>African Americans</subject><subject>Antidepressive Agents, Second-Generation - metabolism</subject><subject>Antidepressive Agents, Second-Generation - therapeutic use</subject><subject>Aryl Hydrocarbon Hydroxylases - metabolism</subject><subject>Biological and medical sciences</subject><subject>Bupropion - analogs & derivatives</subject><subject>Bupropion - metabolism</subject><subject>Bupropion - therapeutic use</subject><subject>Cytochrome P-450 CYP2B6</subject><subject>Double-Blind Method</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Logistic Models</subject><subject>Medical sciences</subject><subject>Odds Ratio</subject><subject>Oxidoreductases, N-Demethylating - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Predictive Value of Tests</subject><subject>Smoking - drug therapy</subject><subject>Smoking Cessation</subject><subject>Treatment Outcome</subject><issn>0009-9236</issn><issn>1532-6535</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc2P0zAQxS0EYsvCkSvKBcElxR_xF4eV2Ijdoq0gokWIk-U6Tms2iYOdwua_J1G7BS6cRjP-zZsnPwCeIzhHkIg3pu76OYYIz5FgD8AMUYJTRgl9CGYQQplKTNgZeBLj97HNpBCPwRkmKJMSixlY5d8KfMkS3ZbJ5b4LvnO-fRWTVeNvXbtNcxuj7sdZUux0aLTxtd8Ob5P1ziaffW0TXyWLoQz-btjcrz8FjypdR_vsWM_Bl6v363yRLj9df8jfLVNDiWDpBjIhLLImMxbBTJgNF5BZKhm0iGJeMWkk4rAsK0lNVVbIIgkxEyxjhDNEzsHFQbfbbxpbGtv2QdeqC67RYVBeO_XvS-t2aut_KsKxxFCOAq-PAsH_2NvYq8ZFY-tat9bvo0KIC8Yk5HxE0wNqgo8x2Op0BkE1BaGmINQUhBqDGPkXf3s70fc_PwIvj4CORtdV0K1x8Q_HOGWUTULywP1ytR3-f1XlxTpfFuupP5g4mnaxt3enXR1uFeOEU_X147W6yeFqga4KdUN-A6jusfw</recordid><startdate>201212</startdate><enddate>201212</enddate><creator>Zhu, A Z X</creator><creator>Cox, L S</creator><creator>Nollen, N</creator><creator>Faseru, B</creator><creator>Okuyemi, K S</creator><creator>Ahluwalia, J S</creator><creator>Benowitz, N L</creator><creator>Tyndale, R F</creator><general>Blackwell Publishing Ltd</general><general>Nature Publishing Group</general><scope>BSCLL</scope><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>201212</creationdate><title>CYP2B6 and Bupropion's Smoking-Cessation Pharmacology: The Role of Hydroxybupropion</title><author>Zhu, A Z X ; Cox, L S ; Nollen, N ; Faseru, B ; Okuyemi, K S ; Ahluwalia, J S ; Benowitz, N L ; Tyndale, R F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5386-b0688e1ec4ce1048cb7806e5960e1527f69c9170ddf95cfdf1e19026864637613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>African Americans</topic><topic>Antidepressive Agents, Second-Generation - metabolism</topic><topic>Antidepressive Agents, Second-Generation - therapeutic use</topic><topic>Aryl Hydrocarbon Hydroxylases - metabolism</topic><topic>Biological and medical sciences</topic><topic>Bupropion - analogs & derivatives</topic><topic>Bupropion - metabolism</topic><topic>Bupropion - therapeutic use</topic><topic>Cytochrome P-450 CYP2B6</topic><topic>Double-Blind Method</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Logistic Models</topic><topic>Medical sciences</topic><topic>Odds Ratio</topic><topic>Oxidoreductases, N-Demethylating - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Predictive Value of Tests</topic><topic>Smoking - drug therapy</topic><topic>Smoking Cessation</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhu, A Z X</creatorcontrib><creatorcontrib>Cox, L S</creatorcontrib><creatorcontrib>Nollen, N</creatorcontrib><creatorcontrib>Faseru, B</creatorcontrib><creatorcontrib>Okuyemi, K S</creatorcontrib><creatorcontrib>Ahluwalia, J S</creatorcontrib><creatorcontrib>Benowitz, N L</creatorcontrib><creatorcontrib>Tyndale, R F</creatorcontrib><collection>Istex</collection><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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhu, A Z X</au><au>Cox, L S</au><au>Nollen, N</au><au>Faseru, B</au><au>Okuyemi, K S</au><au>Ahluwalia, J S</au><au>Benowitz, N L</au><au>Tyndale, R F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CYP2B6 and Bupropion's Smoking-Cessation Pharmacology: The Role of Hydroxybupropion</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><addtitle>Clinical Pharmacology & Therapeutics</addtitle><date>2012-12</date><risdate>2012</risdate><volume>92</volume><issue>6</issue><spage>771</spage><epage>777</epage><pages>771-777</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><coden>CLPTAT</coden><abstract>Bupropion is indicated to promote smoking cessation. Animal studies suggest that the pharmacologic activity of bupropion can be mediated by its major metabolite, hydroxybupropion. We measured plasma bupropion and its metabolite levels in a double‐blind, placebo controlled, randomized smoking‐cessation trial. Among the treatment‐adherent individuals, higher hydroxybupropion concentrations (per μg/ml) resulted in better smoking‐cessation outcomes (week 3, 7, and 26 odds ratio (OR) = 2.82, 2.96, and 2.37, respectively, P = 0.005–0.040); this was not observed with bupropion levels (OR = 1.00–1.03, P = 0.59–0.90). Genetic variation in CYP2B6, the enzyme that metabolizes bupropion to hydroxybupropion, was identified as a significant source of variability in hydroxybupropion formation. Our data indicate that hydroxybupropion contributes to the pharmacologic effects of bupropion for smoking cessation, and that variability in response to bupropion treatment is related to variability in CYP2B6‐mediated hydroxybupropion formation. These findings suggest that dosing of bupropion to achieve a hydroxybupropion level of 0.7 μg/ml or increasing bupropion dose for CYP2B6 slow metabolizers could improve bupropion's cessation outcomes.
Clinical Pharmacology & Therapeutics (2012); 92 6, 771–777. doi:10.1038/clpt.2012.186</abstract><cop>Basingstoke</cop><pub>Blackwell Publishing Ltd</pub><pmid>23149928</pmid><doi>10.1038/clpt.2012.186</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Clinical pharmacology and therapeutics, 2012-12, Vol.92 (6), p.771-777 |
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| subjects | African Americans Antidepressive Agents, Second-Generation - metabolism Antidepressive Agents, Second-Generation - therapeutic use Aryl Hydrocarbon Hydroxylases - metabolism Biological and medical sciences Bupropion - analogs & derivatives Bupropion - metabolism Bupropion - therapeutic use Cytochrome P-450 CYP2B6 Double-Blind Method Humans Kinetics Logistic Models Medical sciences Odds Ratio Oxidoreductases, N-Demethylating - metabolism Pharmacology. Drug treatments Predictive Value of Tests Smoking - drug therapy Smoking Cessation Treatment Outcome |
| title | CYP2B6 and Bupropion's Smoking-Cessation Pharmacology: The Role of Hydroxybupropion |
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