Citalopram and desmethylcitalopram in vitro: human cytochromes mediating transformation, and cytochrome inhibitory effects
Background: Biotransformation of citalopram (CT), a newly available selective serotonin reuptake inhibitor antidepressant, to its principal metabolite, desmethycitalopram (DCT), and the capacity of CT and DCT to inhibit human cytochromes P450, were studied in vitro. Methods: Formation of DCT from CT...
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| Veröffentlicht in: | Biological psychiatry (1969) 1999-09, Vol.46 (6), p.839-849 |
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| container_title | Biological psychiatry (1969) |
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| creator | von Moltke, Lisa L. Greenblatt, David J. Grassi, Jeffrey M. Granda, Brian W. Venkatakrishnan, Karthik Duan, Su Xiang Fogelman, Steven M. Harmatz, Jerold S. Shader, Richard I. |
| description | Background: Biotransformation of citalopram (CT), a newly available selective serotonin reuptake inhibitor antidepressant, to its principal metabolite, desmethycitalopram (DCT), and the capacity of CT and DCT to inhibit human cytochromes P450, were studied in vitro.
Methods: Formation of DCT from CT was evaluated using human liver microsomes and microsomes from cDNA-transfected human lymphoblastoid cells. Cytochrome inhibition by CT and DCT in liver microsomes was studied using isoform-specific index reactions.
Results: Formation of DCT from CT in liver microsomes had a mean apparent K
m of 174 μmol/L. Coincubation with 1 μmol/L ketoconazole reduced reaction velocity to 46 to 58% of control values, while omeprazole, 10 μmol/L, reduced velocity to 80% of control. Quinidine produced minimal inhibition. DCT was formed from CT by heterologously expressed human P450-2D6, -2C19, -3A4. After accounting for the relative abundance of individual cytochromes, 3A4 and 2C19 were estimated to make major contributions to net reaction velocity, with a possible contribution of 2D6 at therapeutic CT concentrations. CT and DCT themselves produced negligible inhibition of 2C9, 2E1, and 3A, and only weak inhibition of 1A2, 2C19, and 2D6.
Conclusions: Formation of DCT from CT is mediated mainly by P450-3A4 and 2C19, with an additional contribution of 2D6. CT at therapeutic doses in humans may produce a small degree of inhibition of P450-1A2, -2C19, and -2D6, but negligible inhibition of P450-2C9, -2E1, and -3A. |
| doi_str_mv | 10.1016/S0006-3223(98)00353-9 |
| format | Article |
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Methods: Formation of DCT from CT was evaluated using human liver microsomes and microsomes from cDNA-transfected human lymphoblastoid cells. Cytochrome inhibition by CT and DCT in liver microsomes was studied using isoform-specific index reactions.
Results: Formation of DCT from CT in liver microsomes had a mean apparent K
m of 174 μmol/L. Coincubation with 1 μmol/L ketoconazole reduced reaction velocity to 46 to 58% of control values, while omeprazole, 10 μmol/L, reduced velocity to 80% of control. Quinidine produced minimal inhibition. DCT was formed from CT by heterologously expressed human P450-2D6, -2C19, -3A4. After accounting for the relative abundance of individual cytochromes, 3A4 and 2C19 were estimated to make major contributions to net reaction velocity, with a possible contribution of 2D6 at therapeutic CT concentrations. CT and DCT themselves produced negligible inhibition of 2C9, 2E1, and 3A, and only weak inhibition of 1A2, 2C19, and 2D6.
Conclusions: Formation of DCT from CT is mediated mainly by P450-3A4 and 2C19, with an additional contribution of 2D6. CT at therapeutic doses in humans may produce a small degree of inhibition of P450-1A2, -2C19, and -2D6, but negligible inhibition of P450-2C9, -2E1, and -3A.</description><identifier>ISSN: 0006-3223</identifier><identifier>EISSN: 1873-2402</identifier><identifier>DOI: 10.1016/S0006-3223(98)00353-9</identifier><identifier>PMID: 10494454</identifier><identifier>CODEN: BIPCBF</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>Biological and medical sciences ; Biotransformation - physiology ; Cell Line, Transformed - drug effects ; Cells, Cultured ; Chromatography, High Pressure Liquid - methods ; Citalopram ; Citalopram - analogs & derivatives ; Citalopram - pharmacokinetics ; Cytochromes - metabolism ; cytochromes P450 ; DNA, Complementary - drug effects ; drug interactions ; drug metabolism ; Humans ; In Vitro Techniques ; Medical sciences ; Microsomes, Liver - metabolism ; Neuropharmacology ; Pharmacology. Drug treatments ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) ; Psychology. Psychoanalysis. Psychiatry ; Psychopharmacology ; selective serotonin reuptake inhibitor ; Serotonin Uptake Inhibitors - pharmacokinetics ; Transfection - drug effects</subject><ispartof>Biological psychiatry (1969), 1999-09, Vol.46 (6), p.839-849</ispartof><rights>1999 Society of Biological Psychiatry</rights><rights>1999 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c456t-f2cb3a0a7b406190c8f5002026ba2e4c8a84a68668a44cb59e6829f949a734983</citedby><cites>FETCH-LOGICAL-c456t-f2cb3a0a7b406190c8f5002026ba2e4c8a84a68668a44cb59e6829f949a734983</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0006322398003539$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1939312$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10494454$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>von Moltke, Lisa L.</creatorcontrib><creatorcontrib>Greenblatt, David J.</creatorcontrib><creatorcontrib>Grassi, Jeffrey M.</creatorcontrib><creatorcontrib>Granda, Brian W.</creatorcontrib><creatorcontrib>Venkatakrishnan, Karthik</creatorcontrib><creatorcontrib>Duan, Su Xiang</creatorcontrib><creatorcontrib>Fogelman, Steven M.</creatorcontrib><creatorcontrib>Harmatz, Jerold S.</creatorcontrib><creatorcontrib>Shader, Richard I.</creatorcontrib><title>Citalopram and desmethylcitalopram in vitro: human cytochromes mediating transformation, and cytochrome inhibitory effects</title><title>Biological psychiatry (1969)</title><addtitle>Biol Psychiatry</addtitle><description>Background: Biotransformation of citalopram (CT), a newly available selective serotonin reuptake inhibitor antidepressant, to its principal metabolite, desmethycitalopram (DCT), and the capacity of CT and DCT to inhibit human cytochromes P450, were studied in vitro.
Methods: Formation of DCT from CT was evaluated using human liver microsomes and microsomes from cDNA-transfected human lymphoblastoid cells. Cytochrome inhibition by CT and DCT in liver microsomes was studied using isoform-specific index reactions.
Results: Formation of DCT from CT in liver microsomes had a mean apparent K
m of 174 μmol/L. Coincubation with 1 μmol/L ketoconazole reduced reaction velocity to 46 to 58% of control values, while omeprazole, 10 μmol/L, reduced velocity to 80% of control. Quinidine produced minimal inhibition. DCT was formed from CT by heterologously expressed human P450-2D6, -2C19, -3A4. After accounting for the relative abundance of individual cytochromes, 3A4 and 2C19 were estimated to make major contributions to net reaction velocity, with a possible contribution of 2D6 at therapeutic CT concentrations. CT and DCT themselves produced negligible inhibition of 2C9, 2E1, and 3A, and only weak inhibition of 1A2, 2C19, and 2D6.
Conclusions: Formation of DCT from CT is mediated mainly by P450-3A4 and 2C19, with an additional contribution of 2D6. CT at therapeutic doses in humans may produce a small degree of inhibition of P450-1A2, -2C19, and -2D6, but negligible inhibition of P450-2C9, -2E1, and -3A.</description><subject>Biological and medical sciences</subject><subject>Biotransformation - physiology</subject><subject>Cell Line, Transformed - drug effects</subject><subject>Cells, Cultured</subject><subject>Chromatography, High Pressure Liquid - methods</subject><subject>Citalopram</subject><subject>Citalopram - analogs & derivatives</subject><subject>Citalopram - pharmacokinetics</subject><subject>Cytochromes - metabolism</subject><subject>cytochromes P450</subject><subject>DNA, Complementary - drug effects</subject><subject>drug interactions</subject><subject>drug metabolism</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Medical sciences</subject><subject>Microsomes, Liver - metabolism</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopharmacology</subject><subject>selective serotonin reuptake inhibitor</subject><subject>Serotonin Uptake Inhibitors - pharmacokinetics</subject><subject>Transfection - drug effects</subject><issn>0006-3223</issn><issn>1873-2402</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE2LFDEQhoO4uLOrP0Hpg8gKtlY-Op14ERnUXVjwoJ5DdSZxIt2dMckszP56szOD481TUcVTbxUPIc8pvKVA5btvACBbzhi_0uo1AO94qx-RBVU9b5kA9pgs_iLn5CLnX7XtGaNPyDkFoYXoxILcL0PBMW4STg3Oq2bl8uTKejfa0zzMzV0oKb5v1tsJ58buSrTrFCeXm8mtApYw_2xKwjn7mKbaxvnNPu1E1pB1GEKJadc4750t-Sk58zhm9-xYL8mPz5--L6_b269fbpYfb1srOllaz-zAEbAfBEiqwSrfATBgckDmhFWoBEolpUIh7NBpJxXTXguNPRda8Uvy6pC7SfH31uVippCtG0ecXdxm0wN0jHJewe4A2hRzTs6bTQoTpp2hYB6km71082DUaGX20o2uey-OB7ZD9fHP1sFyBV4eAcwWR19N2ZBPnOaaU1axDwfMVRt3wSWTbXCzrYpTFWZWMfznkz-zoaBO</recordid><startdate>19990915</startdate><enddate>19990915</enddate><creator>von Moltke, Lisa L.</creator><creator>Greenblatt, David J.</creator><creator>Grassi, Jeffrey M.</creator><creator>Granda, Brian W.</creator><creator>Venkatakrishnan, Karthik</creator><creator>Duan, Su Xiang</creator><creator>Fogelman, Steven M.</creator><creator>Harmatz, Jerold S.</creator><creator>Shader, Richard I.</creator><general>Elsevier Inc</general><general>Elsevier 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>7X8</scope></search><sort><creationdate>19990915</creationdate><title>Citalopram and desmethylcitalopram in vitro: human cytochromes mediating transformation, and cytochrome inhibitory effects</title><author>von Moltke, Lisa L. ; Greenblatt, David J. ; Grassi, Jeffrey M. ; Granda, Brian W. ; Venkatakrishnan, Karthik ; Duan, Su Xiang ; Fogelman, Steven M. ; Harmatz, Jerold S. ; Shader, Richard I.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c456t-f2cb3a0a7b406190c8f5002026ba2e4c8a84a68668a44cb59e6829f949a734983</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Biological and medical sciences</topic><topic>Biotransformation - physiology</topic><topic>Cell Line, Transformed - drug effects</topic><topic>Cells, Cultured</topic><topic>Chromatography, High Pressure Liquid - methods</topic><topic>Citalopram</topic><topic>Citalopram - analogs & derivatives</topic><topic>Citalopram - pharmacokinetics</topic><topic>Cytochromes - metabolism</topic><topic>cytochromes P450</topic><topic>DNA, Complementary - drug effects</topic><topic>drug interactions</topic><topic>drug metabolism</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Medical sciences</topic><topic>Microsomes, Liver - metabolism</topic><topic>Neuropharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</topic><topic>Psychology. Psychoanalysis. Psychiatry</topic><topic>Psychopharmacology</topic><topic>selective serotonin reuptake inhibitor</topic><topic>Serotonin Uptake Inhibitors - pharmacokinetics</topic><topic>Transfection - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>von Moltke, Lisa L.</creatorcontrib><creatorcontrib>Greenblatt, David J.</creatorcontrib><creatorcontrib>Grassi, Jeffrey M.</creatorcontrib><creatorcontrib>Granda, Brian W.</creatorcontrib><creatorcontrib>Venkatakrishnan, Karthik</creatorcontrib><creatorcontrib>Duan, Su Xiang</creatorcontrib><creatorcontrib>Fogelman, Steven M.</creatorcontrib><creatorcontrib>Harmatz, Jerold S.</creatorcontrib><creatorcontrib>Shader, Richard I.</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>MEDLINE - Academic</collection><jtitle>Biological psychiatry (1969)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>von Moltke, Lisa L.</au><au>Greenblatt, David J.</au><au>Grassi, Jeffrey M.</au><au>Granda, Brian W.</au><au>Venkatakrishnan, Karthik</au><au>Duan, Su Xiang</au><au>Fogelman, Steven M.</au><au>Harmatz, Jerold S.</au><au>Shader, Richard I.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Citalopram and desmethylcitalopram in vitro: human cytochromes mediating transformation, and cytochrome inhibitory effects</atitle><jtitle>Biological psychiatry (1969)</jtitle><addtitle>Biol Psychiatry</addtitle><date>1999-09-15</date><risdate>1999</risdate><volume>46</volume><issue>6</issue><spage>839</spage><epage>849</epage><pages>839-849</pages><issn>0006-3223</issn><eissn>1873-2402</eissn><coden>BIPCBF</coden><abstract>Background: Biotransformation of citalopram (CT), a newly available selective serotonin reuptake inhibitor antidepressant, to its principal metabolite, desmethycitalopram (DCT), and the capacity of CT and DCT to inhibit human cytochromes P450, were studied in vitro.
Methods: Formation of DCT from CT was evaluated using human liver microsomes and microsomes from cDNA-transfected human lymphoblastoid cells. Cytochrome inhibition by CT and DCT in liver microsomes was studied using isoform-specific index reactions.
Results: Formation of DCT from CT in liver microsomes had a mean apparent K
m of 174 μmol/L. Coincubation with 1 μmol/L ketoconazole reduced reaction velocity to 46 to 58% of control values, while omeprazole, 10 μmol/L, reduced velocity to 80% of control. Quinidine produced minimal inhibition. DCT was formed from CT by heterologously expressed human P450-2D6, -2C19, -3A4. After accounting for the relative abundance of individual cytochromes, 3A4 and 2C19 were estimated to make major contributions to net reaction velocity, with a possible contribution of 2D6 at therapeutic CT concentrations. CT and DCT themselves produced negligible inhibition of 2C9, 2E1, and 3A, and only weak inhibition of 1A2, 2C19, and 2D6.
Conclusions: Formation of DCT from CT is mediated mainly by P450-3A4 and 2C19, with an additional contribution of 2D6. CT at therapeutic doses in humans may produce a small degree of inhibition of P450-1A2, -2C19, and -2D6, but negligible inhibition of P450-2C9, -2E1, and -3A.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>10494454</pmid><doi>10.1016/S0006-3223(98)00353-9</doi><tpages>11</tpages></addata></record> |
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| subjects | Biological and medical sciences Biotransformation - physiology Cell Line, Transformed - drug effects Cells, Cultured Chromatography, High Pressure Liquid - methods Citalopram Citalopram - analogs & derivatives Citalopram - pharmacokinetics Cytochromes - metabolism cytochromes P450 DNA, Complementary - drug effects drug interactions drug metabolism Humans In Vitro Techniques Medical sciences Microsomes, Liver - metabolism Neuropharmacology Pharmacology. Drug treatments Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology selective serotonin reuptake inhibitor Serotonin Uptake Inhibitors - pharmacokinetics Transfection - drug effects |
| title | Citalopram and desmethylcitalopram in vitro: human cytochromes mediating transformation, and cytochrome inhibitory effects |
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