Kinetics of the in vivo interconversion of the carboxylate and lactone forms of irinotecan (CPT-11) and of its metabolite SN-38 in patients
The kinetics of the in vivo interconversion of the carboxylate and lactone forms of the prodrug irinotecan, 7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin (CPT-11), and its active metabolite SN-38 were studied in five patients using a HPLC method that allows the simultaneous dete...
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Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 1994-12, Vol.54 (24), p.6330-6333 |
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creator | Rivory, L P Chatelut, E Canal, P Mathieu-Boué, A Robert, J |
description | The kinetics of the in vivo interconversion of the carboxylate and lactone forms of the prodrug irinotecan, 7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin (CPT-11), and its active metabolite SN-38 were studied in five patients using a HPLC method that allows the simultaneous determination of all four compounds and detects any hydrolysis of lactones due to inadequate sample handling and storage. The apparent conversion of CPT-11 lactone to the carboxylate in vivo was rapid with a mean half-life of 9.5 min; the carboxylate became the predominant form of plasma CPT-11 soon after the end of the infusion. The ratio of the area under the plasma concentration-time curves of the lactone to total CPT-11 was 36.8 +/- 3.5% (SD). In contrast, SN-38 was present predominantly as the lactone at all times and with little interpatient variability (lactone/total area under the plasma concentration-time curve ratio, 64.0 +/- 3.4%). This may explain in part the promising activity of CPT-11 because CPT derivatives are active against their target, topoisomerase I, only in their lactone form. |
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The apparent conversion of CPT-11 lactone to the carboxylate in vivo was rapid with a mean half-life of 9.5 min; the carboxylate became the predominant form of plasma CPT-11 soon after the end of the infusion. The ratio of the area under the plasma concentration-time curves of the lactone to total CPT-11 was 36.8 +/- 3.5% (SD). In contrast, SN-38 was present predominantly as the lactone at all times and with little interpatient variability (lactone/total area under the plasma concentration-time curve ratio, 64.0 +/- 3.4%). This may explain in part the promising activity of CPT-11 because CPT derivatives are active against their target, topoisomerase I, only in their lactone form.</description><identifier>ISSN: 0008-5472</identifier><identifier>PMID: 7987823</identifier><language>eng</language><publisher>United States</publisher><subject>Aged ; Antineoplastic Agents, Phytogenic - blood ; Antineoplastic Agents, Phytogenic - chemistry ; Antineoplastic Agents, Phytogenic - metabolism ; Camptothecin - analogs & derivatives ; Camptothecin - blood ; Camptothecin - chemistry ; Camptothecin - metabolism ; Female ; Half-Life ; Humans ; Male ; Middle Aged ; Prodrugs - chemistry ; Prodrugs - metabolism</subject><ispartof>Cancer research (Chicago, Ill.), 1994-12, Vol.54 (24), p.6330-6333</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7987823$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rivory, L P</creatorcontrib><creatorcontrib>Chatelut, E</creatorcontrib><creatorcontrib>Canal, P</creatorcontrib><creatorcontrib>Mathieu-Boué, A</creatorcontrib><creatorcontrib>Robert, J</creatorcontrib><title>Kinetics of the in vivo interconversion of the carboxylate and lactone forms of irinotecan (CPT-11) and of its metabolite SN-38 in patients</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>The kinetics of the in vivo interconversion of the carboxylate and lactone forms of the prodrug irinotecan, 7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin (CPT-11), and its active metabolite SN-38 were studied in five patients using a HPLC method that allows the simultaneous determination of all four compounds and detects any hydrolysis of lactones due to inadequate sample handling and storage. The apparent conversion of CPT-11 lactone to the carboxylate in vivo was rapid with a mean half-life of 9.5 min; the carboxylate became the predominant form of plasma CPT-11 soon after the end of the infusion. The ratio of the area under the plasma concentration-time curves of the lactone to total CPT-11 was 36.8 +/- 3.5% (SD). In contrast, SN-38 was present predominantly as the lactone at all times and with little interpatient variability (lactone/total area under the plasma concentration-time curve ratio, 64.0 +/- 3.4%). This may explain in part the promising activity of CPT-11 because CPT derivatives are active against their target, topoisomerase I, only in their lactone form.</description><subject>Aged</subject><subject>Antineoplastic Agents, Phytogenic - blood</subject><subject>Antineoplastic Agents, Phytogenic - chemistry</subject><subject>Antineoplastic Agents, Phytogenic - metabolism</subject><subject>Camptothecin - analogs & derivatives</subject><subject>Camptothecin - blood</subject><subject>Camptothecin - chemistry</subject><subject>Camptothecin - metabolism</subject><subject>Female</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Prodrugs - chemistry</subject><subject>Prodrugs - metabolism</subject><issn>0008-5472</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kM1KAzEUhWeh1Fp9BCEr0cVAMklm0qUUtWJRwboe8nNDIzNJTdJin8GXdlrr6nA43z0H7kkxxhiLkrOmOivOU_ocLCeYj4pRMxWNqOi4-Hl2HrLTCQWL8gqQ82jrtmHQDFEHv4WYXPD_sZZRhe9dJzMg6Q3qpM7BA7Ih9ocOF50PGbT06Gb2tiwJuT2A-ygn1EOWKnRuOH9_KanY761lduBzuihOrewSXB51Unw83C9n83Lx-vg0u1uUq4rhXFqKuVa0oUxWGGxtqK0sVTXnBjNs2LSagmKE15hgZQ0jzDRCaWY4BQoE00lx_de7juFrAym3vUsauk56CJvUNrUQlSD1AF4dwY3qwbTr6HoZd-3xe_QXrnFqww</recordid><startdate>19941215</startdate><enddate>19941215</enddate><creator>Rivory, L P</creator><creator>Chatelut, E</creator><creator>Canal, P</creator><creator>Mathieu-Boué, A</creator><creator>Robert, J</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>19941215</creationdate><title>Kinetics of the in vivo interconversion of the carboxylate and lactone forms of irinotecan (CPT-11) and of its metabolite SN-38 in patients</title><author>Rivory, L P ; Chatelut, E ; Canal, P ; Mathieu-Boué, A ; Robert, J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h240t-f305cb3734a20ef6d3f2f3b655d040d4929eb4156010bfd414d78bc4d53e3e103</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>Aged</topic><topic>Antineoplastic Agents, Phytogenic - blood</topic><topic>Antineoplastic Agents, Phytogenic - chemistry</topic><topic>Antineoplastic Agents, Phytogenic - metabolism</topic><topic>Camptothecin - analogs & derivatives</topic><topic>Camptothecin - blood</topic><topic>Camptothecin - chemistry</topic><topic>Camptothecin - metabolism</topic><topic>Female</topic><topic>Half-Life</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Prodrugs - chemistry</topic><topic>Prodrugs - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rivory, L P</creatorcontrib><creatorcontrib>Chatelut, E</creatorcontrib><creatorcontrib>Canal, P</creatorcontrib><creatorcontrib>Mathieu-Boué, A</creatorcontrib><creatorcontrib>Robert, J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rivory, L P</au><au>Chatelut, E</au><au>Canal, P</au><au>Mathieu-Boué, A</au><au>Robert, J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Kinetics of the in vivo interconversion of the carboxylate and lactone forms of irinotecan (CPT-11) and of its metabolite SN-38 in patients</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>1994-12-15</date><risdate>1994</risdate><volume>54</volume><issue>24</issue><spage>6330</spage><epage>6333</epage><pages>6330-6333</pages><issn>0008-5472</issn><abstract>The kinetics of the in vivo interconversion of the carboxylate and lactone forms of the prodrug irinotecan, 7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin (CPT-11), and its active metabolite SN-38 were studied in five patients using a HPLC method that allows the simultaneous determination of all four compounds and detects any hydrolysis of lactones due to inadequate sample handling and storage. The apparent conversion of CPT-11 lactone to the carboxylate in vivo was rapid with a mean half-life of 9.5 min; the carboxylate became the predominant form of plasma CPT-11 soon after the end of the infusion. The ratio of the area under the plasma concentration-time curves of the lactone to total CPT-11 was 36.8 +/- 3.5% (SD). In contrast, SN-38 was present predominantly as the lactone at all times and with little interpatient variability (lactone/total area under the plasma concentration-time curve ratio, 64.0 +/- 3.4%). This may explain in part the promising activity of CPT-11 because CPT derivatives are active against their target, topoisomerase I, only in their lactone form.</abstract><cop>United States</cop><pmid>7987823</pmid><tpages>4</tpages></addata></record> |
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subjects | Aged Antineoplastic Agents, Phytogenic - blood Antineoplastic Agents, Phytogenic - chemistry Antineoplastic Agents, Phytogenic - metabolism Camptothecin - analogs & derivatives Camptothecin - blood Camptothecin - chemistry Camptothecin - metabolism Female Half-Life Humans Male Middle Aged Prodrugs - chemistry Prodrugs - metabolism |
title | Kinetics of the in vivo interconversion of the carboxylate and lactone forms of irinotecan (CPT-11) and of its metabolite SN-38 in patients |
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