Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone
1. In microsomes prepared from three human livers, methadone competitively inhibited the O‐demethylation of dextromethorphan, a marker substrate for CYP2D6. The apparent Ki value of methadone ranged from 2.5 to 5 microM. 2. Two hundred and fifty‐two (252) white Caucasians, including 210 unrelated he...
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| Veröffentlicht in: | British journal of clinical pharmacology 1993-01, Vol.35 (1), p.30-34 |
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| container_title | British journal of clinical pharmacology |
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| creator | Wu, D. Otton, SV Sproule, BA Busto, U. Inaba, T. Kalow, W. Sellers, EM |
| description | 1. In microsomes prepared from three human livers, methadone competitively inhibited the O‐demethylation of dextromethorphan, a marker substrate for CYP2D6. The apparent Ki value of methadone ranged from 2.5 to 5 microM. 2. Two hundred and fifty‐two (252) white Caucasians, including 210 unrelated healthy volunteers and 42 opiate abusers undergoing treatment with methadone were phenotyped using dextromethorphan as the marker drug. Although the frequency of poor metabolizers was similar in both groups, the extensive metabolizers among the opiate abusers tended to have higher O‐demethylation metabolic ratios and to excrete less of the dose as dextromethorphan metabolites than control extensive metabolizer subjects. These data suggest inhibition of CYP2D6 by methadone in vivo as well. 3. Because methadone is widely used in the treatment of opiate abuse, inhibition of CYP2D6 activity in these patients might contribute to exaggerated response or unexpected toxicity from drugs that are substrates of this enzyme. |
| doi_str_mv | 10.1111/j.1365-2125.1993.tb05666.x |
| format | Article |
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In microsomes prepared from three human livers, methadone competitively inhibited the O‐demethylation of dextromethorphan, a marker substrate for CYP2D6. The apparent Ki value of methadone ranged from 2.5 to 5 microM. 2. Two hundred and fifty‐two (252) white Caucasians, including 210 unrelated healthy volunteers and 42 opiate abusers undergoing treatment with methadone were phenotyped using dextromethorphan as the marker drug. Although the frequency of poor metabolizers was similar in both groups, the extensive metabolizers among the opiate abusers tended to have higher O‐demethylation metabolic ratios and to excrete less of the dose as dextromethorphan metabolites than control extensive metabolizer subjects. These data suggest inhibition of CYP2D6 by methadone in vivo as well. 3. Because methadone is widely used in the treatment of opiate abuse, inhibition of CYP2D6 activity in these patients might contribute to exaggerated response or unexpected toxicity from drugs that are substrates of this enzyme.</description><identifier>ISSN: 0306-5251</identifier><identifier>EISSN: 1365-2125</identifier><identifier>DOI: 10.1111/j.1365-2125.1993.tb05666.x</identifier><identifier>PMID: 8448065</identifier><identifier>CODEN: BCPHBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Science Ltd</publisher><subject>Adolescent ; Adult ; Analgesics ; Biological and medical sciences ; Cytochrome P-450 CYP2D6 ; Cytochrome P-450 Enzyme Inhibitors ; Female ; Humans ; Male ; Medical sciences ; Methadone - metabolism ; Methadone - pharmacology ; Microsomes, Liver - enzymology ; Middle Aged ; Mixed Function Oxygenases - antagonists & inhibitors ; Neuropharmacology ; Pharmacology. Drug treatments</subject><ispartof>British journal of clinical pharmacology, 1993-01, Vol.35 (1), p.30-34</ispartof><rights>1993 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5066-4afedaea7ae3b730ee137a23a61fd971b05fc3abf10271dea22d8470b247dec23</citedby><cites>FETCH-LOGICAL-c5066-4afedaea7ae3b730ee137a23a61fd971b05fc3abf10271dea22d8470b247dec23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,309,310,314,780,784,789,790,885,4050,4051,23930,23931,25140,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4510026$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8448065$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, D.</creatorcontrib><creatorcontrib>Otton, SV</creatorcontrib><creatorcontrib>Sproule, BA</creatorcontrib><creatorcontrib>Busto, U.</creatorcontrib><creatorcontrib>Inaba, T.</creatorcontrib><creatorcontrib>Kalow, W.</creatorcontrib><creatorcontrib>Sellers, EM</creatorcontrib><title>Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone</title><title>British journal of clinical pharmacology</title><addtitle>Br J Clin Pharmacol</addtitle><description>1. In microsomes prepared from three human livers, methadone competitively inhibited the O‐demethylation of dextromethorphan, a marker substrate for CYP2D6. The apparent Ki value of methadone ranged from 2.5 to 5 microM. 2. Two hundred and fifty‐two (252) white Caucasians, including 210 unrelated healthy volunteers and 42 opiate abusers undergoing treatment with methadone were phenotyped using dextromethorphan as the marker drug. Although the frequency of poor metabolizers was similar in both groups, the extensive metabolizers among the opiate abusers tended to have higher O‐demethylation metabolic ratios and to excrete less of the dose as dextromethorphan metabolites than control extensive metabolizer subjects. These data suggest inhibition of CYP2D6 by methadone in vivo as well. 3. Because methadone is widely used in the treatment of opiate abuse, inhibition of CYP2D6 activity in these patients might contribute to exaggerated response or unexpected toxicity from drugs that are substrates of this enzyme.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Analgesics</subject><subject>Biological and medical sciences</subject><subject>Cytochrome P-450 CYP2D6</subject><subject>Cytochrome P-450 Enzyme Inhibitors</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Methadone - metabolism</subject><subject>Methadone - pharmacology</subject><subject>Microsomes, Liver - enzymology</subject><subject>Middle Aged</subject><subject>Mixed Function Oxygenases - antagonists & inhibitors</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</subject><issn>0306-5251</issn><issn>1365-2125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1993</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqVkE9Lw0AQxRdRtFY_ghDEgx4Sd3azm1RQ0fivULAHPXhaJpuNSWmSkqTafHsTGoIe3cssvHlvHj9CToE60L7LhQNcCpsBEw5MJtypQyqklM5mh4wGaZeMKKfSFkzAATmsqgWlwEGKfbLvu65PpRiR62mepGFap0VuFbGVrDPMLd3UhU7KIjPW3BXUYg_SOg8-5u28sMLGykydYFTk5ojsxbiszHE_x-T96fEteLFnr8_T4G5ma0GltF2MTYQGPTQ89Dg1BriHjKOEOJp40LaPNccwBso8iAwyFvmuR0PmepHRjI_JzTZ3tQ4zE2mT1yUu1apMMywbVWCq_ip5mqjP4ksB98H1ZRtwtQ3QZVFVpYkHL1DVMVUL1YFTHTjVMVU9U7VpzSe_rw_WHmKrn_U6VhqXcYm5TqthzRVAKes63G7XvtOlaf5RQN0H8-7HfwAunZMY</recordid><startdate>199301</startdate><enddate>199301</enddate><creator>Wu, D.</creator><creator>Otton, SV</creator><creator>Sproule, BA</creator><creator>Busto, U.</creator><creator>Inaba, T.</creator><creator>Kalow, W.</creator><creator>Sellers, EM</creator><general>Blackwell Science Ltd</general><general>Blackwell Science</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>5PM</scope></search><sort><creationdate>199301</creationdate><title>Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone</title><author>Wu, D. ; Otton, SV ; Sproule, BA ; Busto, U. ; Inaba, T. ; Kalow, W. ; Sellers, EM</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5066-4afedaea7ae3b730ee137a23a61fd971b05fc3abf10271dea22d8470b247dec23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1993</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Analgesics</topic><topic>Biological and medical sciences</topic><topic>Cytochrome P-450 CYP2D6</topic><topic>Cytochrome P-450 Enzyme Inhibitors</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Methadone - metabolism</topic><topic>Methadone - pharmacology</topic><topic>Microsomes, Liver - enzymology</topic><topic>Middle Aged</topic><topic>Mixed Function Oxygenases - antagonists & inhibitors</topic><topic>Neuropharmacology</topic><topic>Pharmacology. Drug treatments</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, D.</creatorcontrib><creatorcontrib>Otton, SV</creatorcontrib><creatorcontrib>Sproule, BA</creatorcontrib><creatorcontrib>Busto, U.</creatorcontrib><creatorcontrib>Inaba, T.</creatorcontrib><creatorcontrib>Kalow, W.</creatorcontrib><creatorcontrib>Sellers, EM</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>PubMed Central (Full Participant titles)</collection><jtitle>British journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wu, D.</au><au>Otton, SV</au><au>Sproule, BA</au><au>Busto, U.</au><au>Inaba, T.</au><au>Kalow, W.</au><au>Sellers, EM</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone</atitle><jtitle>British journal of clinical pharmacology</jtitle><addtitle>Br J Clin Pharmacol</addtitle><date>1993-01</date><risdate>1993</risdate><volume>35</volume><issue>1</issue><spage>30</spage><epage>34</epage><pages>30-34</pages><issn>0306-5251</issn><eissn>1365-2125</eissn><coden>BCPHBM</coden><abstract>1. In microsomes prepared from three human livers, methadone competitively inhibited the O‐demethylation of dextromethorphan, a marker substrate for CYP2D6. The apparent Ki value of methadone ranged from 2.5 to 5 microM. 2. Two hundred and fifty‐two (252) white Caucasians, including 210 unrelated healthy volunteers and 42 opiate abusers undergoing treatment with methadone were phenotyped using dextromethorphan as the marker drug. Although the frequency of poor metabolizers was similar in both groups, the extensive metabolizers among the opiate abusers tended to have higher O‐demethylation metabolic ratios and to excrete less of the dose as dextromethorphan metabolites than control extensive metabolizer subjects. These data suggest inhibition of CYP2D6 by methadone in vivo as well. 3. Because methadone is widely used in the treatment of opiate abuse, inhibition of CYP2D6 activity in these patients might contribute to exaggerated response or unexpected toxicity from drugs that are substrates of this enzyme.</abstract><cop>Oxford, UK</cop><pub>Blackwell Science Ltd</pub><pmid>8448065</pmid><doi>10.1111/j.1365-2125.1993.tb05666.x</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0306-5251 |
| ispartof | British journal of clinical pharmacology, 1993-01, Vol.35 (1), p.30-34 |
| issn | 0306-5251 1365-2125 |
| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adolescent Adult Analgesics Biological and medical sciences Cytochrome P-450 CYP2D6 Cytochrome P-450 Enzyme Inhibitors Female Humans Male Medical sciences Methadone - metabolism Methadone - pharmacology Microsomes, Liver - enzymology Middle Aged Mixed Function Oxygenases - antagonists & inhibitors Neuropharmacology Pharmacology. Drug treatments |
| title | Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone |
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