In Vitro Inhibition and Induction of Human Liver Cytochrome P450 Enzymes by Milnacipran
Milnacipran (Savella) inhibits both norepinephrine and serotonin reuptake and is distinguished by a nearly 3-fold greater potency in inhibiting norepinephrine reuptake in vitro compared with serotonin. We evaluated the ability of milnacipran to inhibit and induce human cytochrome P450 enzymes in vit...
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| Veröffentlicht in: | Drug metabolism and disposition 2009-10, Vol.37 (10), p.2045-2054 |
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| creator | Paris, Brandy L. Ogilvie, Brian W. Scheinkoenig, Julie A. Ndikum-Moffor, Florence Gibson, Remi Parkinson, Andrew |
| description | Milnacipran (Savella) inhibits both norepinephrine and serotonin reuptake and is distinguished by a nearly 3-fold greater potency in inhibiting norepinephrine reuptake in vitro compared with serotonin. We evaluated the ability of milnacipran to inhibit and induce human cytochrome P450 enzymes in vitro. In human liver microsomes, milnacipran did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 (IC50 ≥ 100 μM); whereas, a comparator with dual reuptake properties [duloxetine (Cymbalta)] inhibited CYP2D6 (IC50 = 7 μM) and CYP2B6 (IC50 = 15 μM) with a relatively high potency. Milnacipran inhibited CYP3A4/5 in a substrate-dependent manner (i.e., midazolam 1′-hydroxylation IC50 ≈ 30 μM; testosterone 6β-hydroxylation IC50 ≈ 100 μM); whereas, duloxetine inhibited both CYP3A4/5 activities with equal potency (IC50 = 37 and 38 μM, respectively). Milnacipran produced no time-dependent inhibition (10 times plasma Cmax) produced 2.6- and 2.2-fold increases in CYP2B6 and CYP3A4/5 activity (making it 26 and 34% as effective as phenobarbital and rifampin, respectively). Given these results, milnacipran is not expected to cause clinically significant P450 inhibition or induction. |
| doi_str_mv | 10.1124/dmd.109.028274 |
| format | Article |
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We evaluated the ability of milnacipran to inhibit and induce human cytochrome P450 enzymes in vitro. In human liver microsomes, milnacipran did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 (IC50 ≥ 100 μM); whereas, a comparator with dual reuptake properties [duloxetine (Cymbalta)] inhibited CYP2D6 (IC50 = 7 μM) and CYP2B6 (IC50 = 15 μM) with a relatively high potency. Milnacipran inhibited CYP3A4/5 in a substrate-dependent manner (i.e., midazolam 1′-hydroxylation IC50 ≈ 30 μM; testosterone 6β-hydroxylation IC50 ≈ 100 μM); whereas, duloxetine inhibited both CYP3A4/5 activities with equal potency (IC50 = 37 and 38 μM, respectively). Milnacipran produced no time-dependent inhibition (<10%) of P450 activity, whereas duloxetine produced time-dependent inhibition of CYP1A2, 2B6, 2C19, and 3A4/5. To evaluate P450 induction, freshly isolated human hepatocytes (n = 3) were cultured and treated once daily for 3 days with milnacipran (3, 10, and 30 μM), after which microsomal P450 activities were measured. Whereas positive controls (omeprazole, phenobarbital, and rifampin) caused anticipated P450 induction, milnacipran had minimal effect on CYP1A2, 2C8, 2C9, or 2C19 activity. The highest concentration of milnacipran (30 μM; >10 times plasma Cmax) produced 2.6- and 2.2-fold increases in CYP2B6 and CYP3A4/5 activity (making it 26 and 34% as effective as phenobarbital and rifampin, respectively). Given these results, milnacipran is not expected to cause clinically significant P450 inhibition or induction.</description><identifier>ISSN: 0090-9556</identifier><identifier>EISSN: 1521-009X</identifier><identifier>DOI: 10.1124/dmd.109.028274</identifier><identifier>PMID: 19608694</identifier><identifier>CODEN: DMDSAI</identifier><language>eng</language><publisher>Bethesda, MD: Elsevier Inc</publisher><subject>Aged ; Anti-Ulcer Agents - pharmacology ; Antitubercular Agents - pharmacology ; Biological and medical sciences ; Cyclopropanes - pharmacology ; Cytochrome P-450 CYP1A2 - metabolism ; Cytochrome P-450 CYP2D6 - metabolism ; Cytochrome P-450 CYP3A - metabolism ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System - drug effects ; Cytochrome P-450 Enzyme System - metabolism ; Drug Interactions ; Enzyme Induction - drug effects ; Hepatocytes - drug effects ; Hepatocytes - enzymology ; Humans ; Hypoglycemic Agents - pharmacology ; Male ; Medical sciences ; Microsomes, Liver - drug effects ; Microsomes, Liver - enzymology ; Midazolam - pharmacology ; Middle Aged ; Milnacipran ; Omeprazole - pharmacology ; Pharmacology. Drug treatments ; Serotonin Uptake Inhibitors - pharmacology ; Testosterone - pharmacology</subject><ispartof>Drug metabolism and disposition, 2009-10, Vol.37 (10), p.2045-2054</ispartof><rights>2009 American Society for Pharmacology and Experimental Therapeutics</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c516t-dc17c08d89438ec206a57c153d67ed8e3babedd5659f9b5ba7bbfb2cbe8acebd3</citedby><cites>FETCH-LOGICAL-c516t-dc17c08d89438ec206a57c153d67ed8e3babedd5659f9b5ba7bbfb2cbe8acebd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21965078$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19608694$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Paris, Brandy L.</creatorcontrib><creatorcontrib>Ogilvie, Brian W.</creatorcontrib><creatorcontrib>Scheinkoenig, Julie A.</creatorcontrib><creatorcontrib>Ndikum-Moffor, Florence</creatorcontrib><creatorcontrib>Gibson, Remi</creatorcontrib><creatorcontrib>Parkinson, Andrew</creatorcontrib><title>In Vitro Inhibition and Induction of Human Liver Cytochrome P450 Enzymes by Milnacipran</title><title>Drug metabolism and disposition</title><addtitle>Drug Metab Dispos</addtitle><description>Milnacipran (Savella) inhibits both norepinephrine and serotonin reuptake and is distinguished by a nearly 3-fold greater potency in inhibiting norepinephrine reuptake in vitro compared with serotonin. We evaluated the ability of milnacipran to inhibit and induce human cytochrome P450 enzymes in vitro. In human liver microsomes, milnacipran did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 (IC50 ≥ 100 μM); whereas, a comparator with dual reuptake properties [duloxetine (Cymbalta)] inhibited CYP2D6 (IC50 = 7 μM) and CYP2B6 (IC50 = 15 μM) with a relatively high potency. Milnacipran inhibited CYP3A4/5 in a substrate-dependent manner (i.e., midazolam 1′-hydroxylation IC50 ≈ 30 μM; testosterone 6β-hydroxylation IC50 ≈ 100 μM); whereas, duloxetine inhibited both CYP3A4/5 activities with equal potency (IC50 = 37 and 38 μM, respectively). Milnacipran produced no time-dependent inhibition (<10%) of P450 activity, whereas duloxetine produced time-dependent inhibition of CYP1A2, 2B6, 2C19, and 3A4/5. To evaluate P450 induction, freshly isolated human hepatocytes (n = 3) were cultured and treated once daily for 3 days with milnacipran (3, 10, and 30 μM), after which microsomal P450 activities were measured. Whereas positive controls (omeprazole, phenobarbital, and rifampin) caused anticipated P450 induction, milnacipran had minimal effect on CYP1A2, 2C8, 2C9, or 2C19 activity. The highest concentration of milnacipran (30 μM; >10 times plasma Cmax) produced 2.6- and 2.2-fold increases in CYP2B6 and CYP3A4/5 activity (making it 26 and 34% as effective as phenobarbital and rifampin, respectively). Given these results, milnacipran is not expected to cause clinically significant P450 inhibition or induction.</description><subject>Aged</subject><subject>Anti-Ulcer Agents - pharmacology</subject><subject>Antitubercular Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cyclopropanes - pharmacology</subject><subject>Cytochrome P-450 CYP1A2 - metabolism</subject><subject>Cytochrome P-450 CYP2D6 - metabolism</subject><subject>Cytochrome P-450 CYP3A - metabolism</subject><subject>Cytochrome P-450 Enzyme Inhibitors</subject><subject>Cytochrome P-450 Enzyme System - drug effects</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Drug Interactions</subject><subject>Enzyme Induction - drug effects</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - enzymology</subject><subject>Humans</subject><subject>Hypoglycemic Agents - pharmacology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Microsomes, Liver - drug effects</subject><subject>Microsomes, Liver - enzymology</subject><subject>Midazolam - pharmacology</subject><subject>Middle Aged</subject><subject>Milnacipran</subject><subject>Omeprazole - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Serotonin Uptake Inhibitors - pharmacology</subject><subject>Testosterone - pharmacology</subject><issn>0090-9556</issn><issn>1521-009X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kE1P3DAQhi3UCra0V47Il4pTFjuJE_uIVnystIgeCu3NsscOcbWxV3aWKv31NWRVTj3NjPS8o5kHoTNKlpSW9aUZzJISsSQlL9v6CC0oK2lBiPj5AS1yIYVgrDlBn1L6RQit60ocoxMqGsIbUS_Qj7XHT26MAa9977QbXfBYeZNHs4e3KXT4bj8ojzfuxUa8msYAfQyDxd9qRvC1_zMNNmE94Xu39QrcLir_GX3s1DbZL4d6ih5vrr-v7orNw-16dbUpgNFmLAzQFgg3XNQVt1CSRrEWKKtM01rDbaWVtsawholOaKZVq3WnS9CWK7DaVKdoOe-FGFKKtpO76AYVJ0mJfDUks6HcCzkbyoHzObDb68Gad_ygJANfD4BKoLZdfgZc-seVGWSk5Zm7mLnePfe_XbRy16s4KAjb8DzJqn29oCQ1yySfSZtFvDgbZQJnPViTUzBKE9z_rv0LIQSQJg</recordid><startdate>20091001</startdate><enddate>20091001</enddate><creator>Paris, Brandy L.</creator><creator>Ogilvie, Brian W.</creator><creator>Scheinkoenig, Julie A.</creator><creator>Ndikum-Moffor, Florence</creator><creator>Gibson, Remi</creator><creator>Parkinson, Andrew</creator><general>Elsevier Inc</general><general>American Society for Pharmacology and Experimental Therapeutics</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></search><sort><creationdate>20091001</creationdate><title>In Vitro Inhibition and Induction of Human Liver Cytochrome P450 Enzymes by Milnacipran</title><author>Paris, Brandy L. ; Ogilvie, Brian W. ; Scheinkoenig, Julie A. ; Ndikum-Moffor, Florence ; Gibson, Remi ; Parkinson, Andrew</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c516t-dc17c08d89438ec206a57c153d67ed8e3babedd5659f9b5ba7bbfb2cbe8acebd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Aged</topic><topic>Anti-Ulcer Agents - pharmacology</topic><topic>Antitubercular Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cyclopropanes - pharmacology</topic><topic>Cytochrome P-450 CYP1A2 - metabolism</topic><topic>Cytochrome P-450 CYP2D6 - metabolism</topic><topic>Cytochrome P-450 CYP3A - metabolism</topic><topic>Cytochrome P-450 Enzyme Inhibitors</topic><topic>Cytochrome P-450 Enzyme System - drug effects</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Drug Interactions</topic><topic>Enzyme Induction - drug effects</topic><topic>Hepatocytes - drug effects</topic><topic>Hepatocytes - enzymology</topic><topic>Humans</topic><topic>Hypoglycemic Agents - pharmacology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Microsomes, Liver - drug effects</topic><topic>Microsomes, Liver - enzymology</topic><topic>Midazolam - pharmacology</topic><topic>Middle Aged</topic><topic>Milnacipran</topic><topic>Omeprazole - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Serotonin Uptake Inhibitors - pharmacology</topic><topic>Testosterone - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Paris, Brandy L.</creatorcontrib><creatorcontrib>Ogilvie, Brian W.</creatorcontrib><creatorcontrib>Scheinkoenig, Julie A.</creatorcontrib><creatorcontrib>Ndikum-Moffor, Florence</creatorcontrib><creatorcontrib>Gibson, Remi</creatorcontrib><creatorcontrib>Parkinson, Andrew</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><jtitle>Drug metabolism and disposition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Paris, Brandy L.</au><au>Ogilvie, Brian W.</au><au>Scheinkoenig, Julie A.</au><au>Ndikum-Moffor, Florence</au><au>Gibson, Remi</au><au>Parkinson, Andrew</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In Vitro Inhibition and Induction of Human Liver Cytochrome P450 Enzymes by Milnacipran</atitle><jtitle>Drug metabolism and disposition</jtitle><addtitle>Drug Metab Dispos</addtitle><date>2009-10-01</date><risdate>2009</risdate><volume>37</volume><issue>10</issue><spage>2045</spage><epage>2054</epage><pages>2045-2054</pages><issn>0090-9556</issn><eissn>1521-009X</eissn><coden>DMDSAI</coden><abstract>Milnacipran (Savella) inhibits both norepinephrine and serotonin reuptake and is distinguished by a nearly 3-fold greater potency in inhibiting norepinephrine reuptake in vitro compared with serotonin. We evaluated the ability of milnacipran to inhibit and induce human cytochrome P450 enzymes in vitro. In human liver microsomes, milnacipran did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 (IC50 ≥ 100 μM); whereas, a comparator with dual reuptake properties [duloxetine (Cymbalta)] inhibited CYP2D6 (IC50 = 7 μM) and CYP2B6 (IC50 = 15 μM) with a relatively high potency. Milnacipran inhibited CYP3A4/5 in a substrate-dependent manner (i.e., midazolam 1′-hydroxylation IC50 ≈ 30 μM; testosterone 6β-hydroxylation IC50 ≈ 100 μM); whereas, duloxetine inhibited both CYP3A4/5 activities with equal potency (IC50 = 37 and 38 μM, respectively). Milnacipran produced no time-dependent inhibition (<10%) of P450 activity, whereas duloxetine produced time-dependent inhibition of CYP1A2, 2B6, 2C19, and 3A4/5. To evaluate P450 induction, freshly isolated human hepatocytes (n = 3) were cultured and treated once daily for 3 days with milnacipran (3, 10, and 30 μM), after which microsomal P450 activities were measured. Whereas positive controls (omeprazole, phenobarbital, and rifampin) caused anticipated P450 induction, milnacipran had minimal effect on CYP1A2, 2C8, 2C9, or 2C19 activity. The highest concentration of milnacipran (30 μM; >10 times plasma Cmax) produced 2.6- and 2.2-fold increases in CYP2B6 and CYP3A4/5 activity (making it 26 and 34% as effective as phenobarbital and rifampin, respectively). Given these results, milnacipran is not expected to cause clinically significant P450 inhibition or induction.</abstract><cop>Bethesda, MD</cop><pub>Elsevier Inc</pub><pmid>19608694</pmid><doi>10.1124/dmd.109.028274</doi><tpages>10</tpages></addata></record> |
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| subjects | Aged Anti-Ulcer Agents - pharmacology Antitubercular Agents - pharmacology Biological and medical sciences Cyclopropanes - pharmacology Cytochrome P-450 CYP1A2 - metabolism Cytochrome P-450 CYP2D6 - metabolism Cytochrome P-450 CYP3A - metabolism Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System - drug effects Cytochrome P-450 Enzyme System - metabolism Drug Interactions Enzyme Induction - drug effects Hepatocytes - drug effects Hepatocytes - enzymology Humans Hypoglycemic Agents - pharmacology Male Medical sciences Microsomes, Liver - drug effects Microsomes, Liver - enzymology Midazolam - pharmacology Middle Aged Milnacipran Omeprazole - pharmacology Pharmacology. Drug treatments Serotonin Uptake Inhibitors - pharmacology Testosterone - pharmacology |
| title | In Vitro Inhibition and Induction of Human Liver Cytochrome P450 Enzymes by Milnacipran |
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