Identification of lactams as in vitro metabolites of piperidine-type phenothiazine antipsychotic drugs
The metabolism of the piperidine-type phenothiazine antipsychotic agents thioridazine, mesoridazine and sulforidazine was studied in vitro with 10 000g liver supernatants obtained from rats and dogs. After incubations at 37°C for different time intervals, the incubates were extracted with dichlorome...
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| Veröffentlicht in: | Journal of pharmaceutical and biomedical analysis 1996-04, Vol.14 (6), p.727-738 |
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| creator | Lin, Ge Chu, Ka-Wing Damani, Lyaquatali A. Hawes, Edward M. |
| description | The metabolism of the piperidine-type phenothiazine antipsychotic agents thioridazine, mesoridazine and sulforidazine was studied in vitro with 10 000g liver supernatants obtained from rats and dogs. After incubations at 37°C for different time intervals, the incubates were extracted with dichloromethane and the isolated compounds analyzed by HPLC, direct probe MS and on-line HPLC-MS. Five lactam metabolites of these three drugs were unequivocally identified in the rat in vitro system, but none was found in dog preparations; at least one lactam metabolite was identified for each drug in the rat. The lactams of thioridazine and thioridazine ring sulfoxide were characterized as metabolites of thioridazine for the first time in any system. The other three lactam metabolites, namely the lactams of mesoridazine, sulforidazine and mesoridazine ring sulfoxide, were found in vitro for the first time, although they have been previously reported as in vivo metabolites of these drugs. The results indicate that rat would be a more suitable animal model than dog for further studies on the formation of lactam metabolites of these drugs. |
| doi_str_mv | 10.1016/0731-7085(95)01670-8 |
| format | Article |
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After incubations at 37°C for different time intervals, the incubates were extracted with dichloromethane and the isolated compounds analyzed by HPLC, direct probe MS and on-line HPLC-MS. Five lactam metabolites of these three drugs were unequivocally identified in the rat in vitro system, but none was found in dog preparations; at least one lactam metabolite was identified for each drug in the rat. The lactams of thioridazine and thioridazine ring sulfoxide were characterized as metabolites of thioridazine for the first time in any system. The other three lactam metabolites, namely the lactams of mesoridazine, sulforidazine and mesoridazine ring sulfoxide, were found in vitro for the first time, although they have been previously reported as in vivo metabolites of these drugs. The results indicate that rat would be a more suitable animal model than dog for further studies on the formation of lactam metabolites of these drugs.</description><identifier>ISSN: 0731-7085</identifier><identifier>EISSN: 1873-264X</identifier><identifier>DOI: 10.1016/0731-7085(95)01670-8</identifier><identifier>PMID: 8807548</identifier><identifier>CODEN: JPBADA</identifier><language>eng</language><publisher>Amsterdam: Elsevier B.V</publisher><subject>Animals ; Antipsychotic Agents - metabolism ; Antipsychotic Agents - pharmacokinetics ; Biological and medical sciences ; Biotransformation ; Chromatography, High Pressure Liquid ; Chromatography, Ion Exchange ; Dogs ; Female ; Humans ; In vitro metabolism ; In Vitro Techniques ; Lactam metabolites ; Lactams - analysis ; Lactams - metabolism ; Liver - metabolism ; Male ; Mass Spectrometry ; Medical sciences ; Mesoridazine ; Mesoridazine - pharmacokinetics ; Neuropharmacology ; Pharmacology. Drug treatments ; Phenothiazines - pharmacokinetics ; Piperidines - metabolism ; Piperidines - pharmacokinetics ; Psycholeptics: tranquillizer, neuroleptic ; Psychology. Psychoanalysis. Psychiatry ; Psychopharmacology ; Rats ; Rats, Sprague-Dawley ; Sulforidazine ; Thioridazine ; Thioridazine - pharmacokinetics</subject><ispartof>Journal of pharmaceutical and biomedical analysis, 1996-04, Vol.14 (6), p.727-738</ispartof><rights>1996</rights><rights>1996 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c386t-ea17f00c95ef3e6332cd717d3a29de38826cd657f0e1a5b5ffa27d0ed0d7d2503</citedby><cites>FETCH-LOGICAL-c386t-ea17f00c95ef3e6332cd717d3a29de38826cd657f0e1a5b5ffa27d0ed0d7d2503</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/0731708595016708$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3124269$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8807548$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lin, Ge</creatorcontrib><creatorcontrib>Chu, Ka-Wing</creatorcontrib><creatorcontrib>Damani, Lyaquatali A.</creatorcontrib><creatorcontrib>Hawes, Edward M.</creatorcontrib><title>Identification of lactams as in vitro metabolites of piperidine-type phenothiazine antipsychotic drugs</title><title>Journal of pharmaceutical and biomedical analysis</title><addtitle>J Pharm Biomed Anal</addtitle><description>The metabolism of the piperidine-type phenothiazine antipsychotic agents thioridazine, mesoridazine and sulforidazine was studied in vitro with 10 000g liver supernatants obtained from rats and dogs. After incubations at 37°C for different time intervals, the incubates were extracted with dichloromethane and the isolated compounds analyzed by HPLC, direct probe MS and on-line HPLC-MS. Five lactam metabolites of these three drugs were unequivocally identified in the rat in vitro system, but none was found in dog preparations; at least one lactam metabolite was identified for each drug in the rat. The lactams of thioridazine and thioridazine ring sulfoxide were characterized as metabolites of thioridazine for the first time in any system. The other three lactam metabolites, namely the lactams of mesoridazine, sulforidazine and mesoridazine ring sulfoxide, were found in vitro for the first time, although they have been previously reported as in vivo metabolites of these drugs. The results indicate that rat would be a more suitable animal model than dog for further studies on the formation of lactam metabolites of these drugs.</description><subject>Animals</subject><subject>Antipsychotic Agents - metabolism</subject><subject>Antipsychotic Agents - pharmacokinetics</subject><subject>Biological and medical sciences</subject><subject>Biotransformation</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Chromatography, Ion Exchange</subject><subject>Dogs</subject><subject>Female</subject><subject>Humans</subject><subject>In vitro metabolism</subject><subject>In Vitro Techniques</subject><subject>Lactam metabolites</subject><subject>Lactams - analysis</subject><subject>Lactams - metabolism</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Mass Spectrometry</subject><subject>Medical sciences</subject><subject>Mesoridazine</subject><subject>Mesoridazine - pharmacokinetics</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenothiazines - pharmacokinetics</subject><subject>Piperidines - metabolism</subject><subject>Piperidines - pharmacokinetics</subject><subject>Psycholeptics: tranquillizer, neuroleptic</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Sulforidazine</subject><subject>Thioridazine</subject><subject>Thioridazine - pharmacokinetics</subject><issn>0731-7085</issn><issn>1873-264X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE2LFDEQhoMo67j6DxRyENFDr_nodNIXQRZ1Fxa8KHgLmaTilHR32iSzMPvr7XaGOe6poOqpt4qHkNecXXHGu49MS95oZtT7Xn1YGpo15gnZcKNlI7r211OyOSPPyYtS_jDGFO_bC3JhDNOqNRsSbwNMFSN6VzFNNEU6OF_dWKgrFCd6jzUnOkJ12zRghbIiM86QMeAETT3MQOcdTKnu0D0sLeqWwLkc_C5V9DTk_e_ykjyLbijw6lQvyc-vX35c3zR337_dXn--a7w0XW3AcR0Z872CKKGTUviguQ7SiT6ANEZ0PnRqYYA7tVUxOqEDg8CCDkIxeUneHXPnnP7uoVQ7YvEwDG6CtC9WGym4MP0CtkfQ51RKhmjnjKPLB8uZXfXa1Z1d3dle2f96rVnW3pzy99sRwnnp5HOZvz3NXfFuiNlNHssZk1y0oluvfzpisLi4R8i2eITJQ8AMvtqQ8PE__gGoApjG</recordid><startdate>19960401</startdate><enddate>19960401</enddate><creator>Lin, Ge</creator><creator>Chu, Ka-Wing</creator><creator>Damani, Lyaquatali A.</creator><creator>Hawes, Edward M.</creator><general>Elsevier B.V</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>19960401</creationdate><title>Identification of lactams as in vitro metabolites of piperidine-type phenothiazine antipsychotic drugs</title><author>Lin, Ge ; Chu, Ka-Wing ; Damani, Lyaquatali A. ; Hawes, Edward M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c386t-ea17f00c95ef3e6332cd717d3a29de38826cd657f0e1a5b5ffa27d0ed0d7d2503</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Animals</topic><topic>Antipsychotic Agents - metabolism</topic><topic>Antipsychotic Agents - pharmacokinetics</topic><topic>Biological and medical sciences</topic><topic>Biotransformation</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Chromatography, Ion Exchange</topic><topic>Dogs</topic><topic>Female</topic><topic>Humans</topic><topic>In vitro metabolism</topic><topic>In Vitro Techniques</topic><topic>Lactam metabolites</topic><topic>Lactams - analysis</topic><topic>Lactams - metabolism</topic><topic>Liver - metabolism</topic><topic>Male</topic><topic>Mass Spectrometry</topic><topic>Medical sciences</topic><topic>Mesoridazine</topic><topic>Mesoridazine - pharmacokinetics</topic><topic>Neuropharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenothiazines - pharmacokinetics</topic><topic>Piperidines - metabolism</topic><topic>Piperidines - pharmacokinetics</topic><topic>Psycholeptics: tranquillizer, neuroleptic</topic><topic>Psychology. Psychoanalysis. Psychiatry</topic><topic>Psychopharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Sulforidazine</topic><topic>Thioridazine</topic><topic>Thioridazine - pharmacokinetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lin, Ge</creatorcontrib><creatorcontrib>Chu, Ka-Wing</creatorcontrib><creatorcontrib>Damani, Lyaquatali A.</creatorcontrib><creatorcontrib>Hawes, Edward M.</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>Journal of pharmaceutical and biomedical analysis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lin, Ge</au><au>Chu, Ka-Wing</au><au>Damani, Lyaquatali A.</au><au>Hawes, Edward M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of lactams as in vitro metabolites of piperidine-type phenothiazine antipsychotic drugs</atitle><jtitle>Journal of pharmaceutical and biomedical analysis</jtitle><addtitle>J Pharm Biomed Anal</addtitle><date>1996-04-01</date><risdate>1996</risdate><volume>14</volume><issue>6</issue><spage>727</spage><epage>738</epage><pages>727-738</pages><issn>0731-7085</issn><eissn>1873-264X</eissn><coden>JPBADA</coden><abstract>The metabolism of the piperidine-type phenothiazine antipsychotic agents thioridazine, mesoridazine and sulforidazine was studied in vitro with 10 000g liver supernatants obtained from rats and dogs. After incubations at 37°C for different time intervals, the incubates were extracted with dichloromethane and the isolated compounds analyzed by HPLC, direct probe MS and on-line HPLC-MS. Five lactam metabolites of these three drugs were unequivocally identified in the rat in vitro system, but none was found in dog preparations; at least one lactam metabolite was identified for each drug in the rat. The lactams of thioridazine and thioridazine ring sulfoxide were characterized as metabolites of thioridazine for the first time in any system. The other three lactam metabolites, namely the lactams of mesoridazine, sulforidazine and mesoridazine ring sulfoxide, were found in vitro for the first time, although they have been previously reported as in vivo metabolites of these drugs. The results indicate that rat would be a more suitable animal model than dog for further studies on the formation of lactam metabolites of these drugs.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>8807548</pmid><doi>10.1016/0731-7085(95)01670-8</doi><tpages>12</tpages></addata></record> |
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| subjects | Animals Antipsychotic Agents - metabolism Antipsychotic Agents - pharmacokinetics Biological and medical sciences Biotransformation Chromatography, High Pressure Liquid Chromatography, Ion Exchange Dogs Female Humans In vitro metabolism In Vitro Techniques Lactam metabolites Lactams - analysis Lactams - metabolism Liver - metabolism Male Mass Spectrometry Medical sciences Mesoridazine Mesoridazine - pharmacokinetics Neuropharmacology Pharmacology. Drug treatments Phenothiazines - pharmacokinetics Piperidines - metabolism Piperidines - pharmacokinetics Psycholeptics: tranquillizer, neuroleptic Psychology. Psychoanalysis. Psychiatry Psychopharmacology Rats Rats, Sprague-Dawley Sulforidazine Thioridazine Thioridazine - pharmacokinetics |
| title | Identification of lactams as in vitro metabolites of piperidine-type phenothiazine antipsychotic drugs |
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