Factors Involved in Prolongation of the Terminal Disposition Phase of SN-38: Clinical and Experimental Studies
The active metabolite of irinotecan (CPT-11), 7-ethyl-10-hydroxycamptothecin (SN-38), is either formed through enzymatic cleavage of CPT-11 by carboxyl esterases (CEs) or through cytochrome P-450 3A-mediated oxidation to 7-ethyl-10-[4-(1-piperidino)-1-amino] carbonyloxycamptothecin (NPC) and a subse...
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| Veröffentlicht in: | Clinical cancer research 2000-09, Vol.6 (9), p.3451-3458 |
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| creator | KEHRER, Diederik F. S YAMAMOTO, Wataru VERWEIJ, Jaap DE JONGE, Maja J. A DE BRUIJN, Peter SPARREBOOM, Alex |
| description | The
active metabolite of irinotecan (CPT-11),
7-ethyl-10-hydroxycamptothecin (SN-38), is either formed through
enzymatic cleavage of CPT-11 by carboxyl esterases (CEs) or through
cytochrome P-450 3A-mediated oxidation to
7-ethyl-10-[4-(1-piperidino)-1-amino] carbonyloxycamptothecin (NPC)
and a subsequent conversion by CE. In the liver, SN-38 is
glucuronidated (SN-38G) by UGT1A1, which also conjugates bilirubin.
Fourteen patients were treated with 350 mg/m 2 CPT-11, and
we performed pharmacokinetic analysis during a 500-h collection period.
The half-life and area under the plasma concentration-time curve of
SN-38 were 47 ± 7.9 h and 2.0 ± 0.79μ
m ·h, respectively, both representing a 2-fold increase
as compared with earlier reported estimates (A. Sparreboom et
al. , Clin. Cancer Res., 4: 2747–2754, 1998). As
an explanation for this phenomenon, we noted substantial formation of
SN-38 from CPT-11 and NPC by plasma CE, consistent with the low
circulating levels of NPC observed. In addition, transport studies in
Caco-2 monolayers indicated that nonglucuronidated SN-38 could cross
the membrane from apical to basolateral, indicating the potential for
recirculation processes that can prolong circulation times.
Interestingly, individual levels of fecal β-glucuronidase, which is
known to mediate SN-38G hydrolysis, were not related to any of the
SN-38 kinetic parameters ( r = 0.09;
P = 0.26), suggesting that interindividual
variation in this enzyme is unimportant in explaining SN-38
pharmacokinetic variability. We have also found, in contrast to earlier
data, that SN-38G/SN-38 plasma concentration ratios decrease over time
from ∼7 (up to 50 h) to ∼1 (at 500 h). This decrease
could be explained by the fact that glucuronidation of SN-38 and
bilirubin is increasingly competitive at lower drug levels. In
addition, no evidence was found for SN-38G transport through the Caco-2
cells. Our findings indicate that until now the circulation time of
SN-38 has been underestimated. This is of crucial importance to our
understanding of the clinical action of CPT-11 and for future
pharmacokinetic/pharmacodynamic relationships. |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_72273921</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>72273921</sourcerecordid><originalsourceid>FETCH-LOGICAL-h268t-64d5769d1dbe7857817380eb68f05394da40ebdb81f618c695bff50f7a429faf3</originalsourceid><addsrcrecordid>eNpF0EtLxDAQAOAiiuvrL0gOoqdCHk2TeJP1tSAquJ5L2ky2kW6yJl0f_96oK55mMvMxTGar2COci5LRmm_nHAtZ4orRSbGf0gvGpCK42i0mBCulBJV7hb_W3RhiQjP_FoY3MMh59BjDEPxCjy54FCwae0BziEvn9YAuXVqF5H56j71O8C2e7ksmz9F0cN51GWlv0NXHCqJbgh9z4WlcGwfpsNixekhwtIkHxfP11Xx6W9493MymF3dlT2s5lnVluKiVIaYFIbmQRDCJoa2lxZypyugqv0wria2J7GrFW2s5tkJXVFlt2UFx-jt3FcPrGtLYLF3qYBi0h7BOjaBUMEVJhscbuG6XYJpV3ljHz-bvQhmcbIBO-Wc2at-59O84poLjzM5-We8W_buL0HQZQoyQQMeub-pGNazihH0BrIJ90g</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>72273921</pqid></control><display><type>article</type><title>Factors Involved in Prolongation of the Terminal Disposition Phase of SN-38: Clinical and Experimental Studies</title><source>MEDLINE</source><source>American Association for Cancer Research</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>KEHRER, Diederik F. S ; YAMAMOTO, Wataru ; VERWEIJ, Jaap ; DE JONGE, Maja J. A ; DE BRUIJN, Peter ; SPARREBOOM, Alex</creator><creatorcontrib>KEHRER, Diederik F. S ; YAMAMOTO, Wataru ; VERWEIJ, Jaap ; DE JONGE, Maja J. A ; DE BRUIJN, Peter ; SPARREBOOM, Alex</creatorcontrib><description>The
active metabolite of irinotecan (CPT-11),
7-ethyl-10-hydroxycamptothecin (SN-38), is either formed through
enzymatic cleavage of CPT-11 by carboxyl esterases (CEs) or through
cytochrome P-450 3A-mediated oxidation to
7-ethyl-10-[4-(1-piperidino)-1-amino] carbonyloxycamptothecin (NPC)
and a subsequent conversion by CE. In the liver, SN-38 is
glucuronidated (SN-38G) by UGT1A1, which also conjugates bilirubin.
Fourteen patients were treated with 350 mg/m 2 CPT-11, and
we performed pharmacokinetic analysis during a 500-h collection period.
The half-life and area under the plasma concentration-time curve of
SN-38 were 47 ± 7.9 h and 2.0 ± 0.79μ
m ·h, respectively, both representing a 2-fold increase
as compared with earlier reported estimates (A. Sparreboom et
al. , Clin. Cancer Res., 4: 2747–2754, 1998). As
an explanation for this phenomenon, we noted substantial formation of
SN-38 from CPT-11 and NPC by plasma CE, consistent with the low
circulating levels of NPC observed. In addition, transport studies in
Caco-2 monolayers indicated that nonglucuronidated SN-38 could cross
the membrane from apical to basolateral, indicating the potential for
recirculation processes that can prolong circulation times.
Interestingly, individual levels of fecal β-glucuronidase, which is
known to mediate SN-38G hydrolysis, were not related to any of the
SN-38 kinetic parameters ( r = 0.09;
P = 0.26), suggesting that interindividual
variation in this enzyme is unimportant in explaining SN-38
pharmacokinetic variability. We have also found, in contrast to earlier
data, that SN-38G/SN-38 plasma concentration ratios decrease over time
from ∼7 (up to 50 h) to ∼1 (at 500 h). This decrease
could be explained by the fact that glucuronidation of SN-38 and
bilirubin is increasingly competitive at lower drug levels. In
addition, no evidence was found for SN-38G transport through the Caco-2
cells. Our findings indicate that until now the circulation time of
SN-38 has been underestimated. This is of crucial importance to our
understanding of the clinical action of CPT-11 and for future
pharmacokinetic/pharmacodynamic relationships.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>PMID: 10999728</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Adult ; Aged ; Antineoplastic agents ; Antineoplastic Agents, Phytogenic - blood ; Antineoplastic Agents, Phytogenic - pharmacokinetics ; Biological and medical sciences ; Biotransformation ; Caco-2 Cells - metabolism ; Camptothecin - analogs & derivatives ; Camptothecin - blood ; Camptothecin - pharmacokinetics ; Carboxylic Ester Hydrolases - blood ; Chemotherapy ; Colorectal Neoplasms - blood ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - metabolism ; Feces - enzymology ; Female ; Glucuronidase - metabolism ; Half-Life ; Humans ; Male ; Medical sciences ; Middle Aged ; Oxidation-Reduction ; Pharmacology. Drug treatments</subject><ispartof>Clinical cancer research, 2000-09, Vol.6 (9), p.3451-3458</ispartof><rights>2000 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1502750$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10999728$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>KEHRER, Diederik F. S</creatorcontrib><creatorcontrib>YAMAMOTO, Wataru</creatorcontrib><creatorcontrib>VERWEIJ, Jaap</creatorcontrib><creatorcontrib>DE JONGE, Maja J. A</creatorcontrib><creatorcontrib>DE BRUIJN, Peter</creatorcontrib><creatorcontrib>SPARREBOOM, Alex</creatorcontrib><title>Factors Involved in Prolongation of the Terminal Disposition Phase of SN-38: Clinical and Experimental Studies</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>The
active metabolite of irinotecan (CPT-11),
7-ethyl-10-hydroxycamptothecin (SN-38), is either formed through
enzymatic cleavage of CPT-11 by carboxyl esterases (CEs) or through
cytochrome P-450 3A-mediated oxidation to
7-ethyl-10-[4-(1-piperidino)-1-amino] carbonyloxycamptothecin (NPC)
and a subsequent conversion by CE. In the liver, SN-38 is
glucuronidated (SN-38G) by UGT1A1, which also conjugates bilirubin.
Fourteen patients were treated with 350 mg/m 2 CPT-11, and
we performed pharmacokinetic analysis during a 500-h collection period.
The half-life and area under the plasma concentration-time curve of
SN-38 were 47 ± 7.9 h and 2.0 ± 0.79μ
m ·h, respectively, both representing a 2-fold increase
as compared with earlier reported estimates (A. Sparreboom et
al. , Clin. Cancer Res., 4: 2747–2754, 1998). As
an explanation for this phenomenon, we noted substantial formation of
SN-38 from CPT-11 and NPC by plasma CE, consistent with the low
circulating levels of NPC observed. In addition, transport studies in
Caco-2 monolayers indicated that nonglucuronidated SN-38 could cross
the membrane from apical to basolateral, indicating the potential for
recirculation processes that can prolong circulation times.
Interestingly, individual levels of fecal β-glucuronidase, which is
known to mediate SN-38G hydrolysis, were not related to any of the
SN-38 kinetic parameters ( r = 0.09;
P = 0.26), suggesting that interindividual
variation in this enzyme is unimportant in explaining SN-38
pharmacokinetic variability. We have also found, in contrast to earlier
data, that SN-38G/SN-38 plasma concentration ratios decrease over time
from ∼7 (up to 50 h) to ∼1 (at 500 h). This decrease
could be explained by the fact that glucuronidation of SN-38 and
bilirubin is increasingly competitive at lower drug levels. In
addition, no evidence was found for SN-38G transport through the Caco-2
cells. Our findings indicate that until now the circulation time of
SN-38 has been underestimated. This is of crucial importance to our
understanding of the clinical action of CPT-11 and for future
pharmacokinetic/pharmacodynamic relationships.</description><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents, Phytogenic - blood</subject><subject>Antineoplastic Agents, Phytogenic - pharmacokinetics</subject><subject>Biological and medical sciences</subject><subject>Biotransformation</subject><subject>Caco-2 Cells - metabolism</subject><subject>Camptothecin - analogs & derivatives</subject><subject>Camptothecin - blood</subject><subject>Camptothecin - pharmacokinetics</subject><subject>Carboxylic Ester Hydrolases - blood</subject><subject>Chemotherapy</subject><subject>Colorectal Neoplasms - blood</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>Feces - enzymology</subject><subject>Female</subject><subject>Glucuronidase - metabolism</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Oxidation-Reduction</subject><subject>Pharmacology. Drug treatments</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpF0EtLxDAQAOAiiuvrL0gOoqdCHk2TeJP1tSAquJ5L2ky2kW6yJl0f_96oK55mMvMxTGar2COci5LRmm_nHAtZ4orRSbGf0gvGpCK42i0mBCulBJV7hb_W3RhiQjP_FoY3MMh59BjDEPxCjy54FCwae0BziEvn9YAuXVqF5H56j71O8C2e7ksmz9F0cN51GWlv0NXHCqJbgh9z4WlcGwfpsNixekhwtIkHxfP11Xx6W9493MymF3dlT2s5lnVluKiVIaYFIbmQRDCJoa2lxZypyugqv0wria2J7GrFW2s5tkJXVFlt2UFx-jt3FcPrGtLYLF3qYBi0h7BOjaBUMEVJhscbuG6XYJpV3ljHz-bvQhmcbIBO-Wc2at-59O84poLjzM5-We8W_buL0HQZQoyQQMeub-pGNazihH0BrIJ90g</recordid><startdate>20000901</startdate><enddate>20000901</enddate><creator>KEHRER, Diederik F. S</creator><creator>YAMAMOTO, Wataru</creator><creator>VERWEIJ, Jaap</creator><creator>DE JONGE, Maja J. A</creator><creator>DE BRUIJN, Peter</creator><creator>SPARREBOOM, Alex</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20000901</creationdate><title>Factors Involved in Prolongation of the Terminal Disposition Phase of SN-38: Clinical and Experimental Studies</title><author>KEHRER, Diederik F. S ; YAMAMOTO, Wataru ; VERWEIJ, Jaap ; DE JONGE, Maja J. A ; DE BRUIJN, Peter ; SPARREBOOM, Alex</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h268t-64d5769d1dbe7857817380eb68f05394da40ebdb81f618c695bff50f7a429faf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents, Phytogenic - blood</topic><topic>Antineoplastic Agents, Phytogenic - pharmacokinetics</topic><topic>Biological and medical sciences</topic><topic>Biotransformation</topic><topic>Caco-2 Cells - metabolism</topic><topic>Camptothecin - analogs & derivatives</topic><topic>Camptothecin - blood</topic><topic>Camptothecin - pharmacokinetics</topic><topic>Carboxylic Ester Hydrolases - blood</topic><topic>Chemotherapy</topic><topic>Colorectal Neoplasms - blood</topic><topic>Colorectal Neoplasms - drug therapy</topic><topic>Colorectal Neoplasms - metabolism</topic><topic>Feces - enzymology</topic><topic>Female</topic><topic>Glucuronidase - metabolism</topic><topic>Half-Life</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Oxidation-Reduction</topic><topic>Pharmacology. Drug treatments</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>KEHRER, Diederik F. S</creatorcontrib><creatorcontrib>YAMAMOTO, Wataru</creatorcontrib><creatorcontrib>VERWEIJ, Jaap</creatorcontrib><creatorcontrib>DE JONGE, Maja J. A</creatorcontrib><creatorcontrib>DE BRUIJN, Peter</creatorcontrib><creatorcontrib>SPARREBOOM, Alex</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>MEDLINE - Academic</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>KEHRER, Diederik F. S</au><au>YAMAMOTO, Wataru</au><au>VERWEIJ, Jaap</au><au>DE JONGE, Maja J. A</au><au>DE BRUIJN, Peter</au><au>SPARREBOOM, Alex</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Factors Involved in Prolongation of the Terminal Disposition Phase of SN-38: Clinical and Experimental Studies</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2000-09-01</date><risdate>2000</risdate><volume>6</volume><issue>9</issue><spage>3451</spage><epage>3458</epage><pages>3451-3458</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>The
active metabolite of irinotecan (CPT-11),
7-ethyl-10-hydroxycamptothecin (SN-38), is either formed through
enzymatic cleavage of CPT-11 by carboxyl esterases (CEs) or through
cytochrome P-450 3A-mediated oxidation to
7-ethyl-10-[4-(1-piperidino)-1-amino] carbonyloxycamptothecin (NPC)
and a subsequent conversion by CE. In the liver, SN-38 is
glucuronidated (SN-38G) by UGT1A1, which also conjugates bilirubin.
Fourteen patients were treated with 350 mg/m 2 CPT-11, and
we performed pharmacokinetic analysis during a 500-h collection period.
The half-life and area under the plasma concentration-time curve of
SN-38 were 47 ± 7.9 h and 2.0 ± 0.79μ
m ·h, respectively, both representing a 2-fold increase
as compared with earlier reported estimates (A. Sparreboom et
al. , Clin. Cancer Res., 4: 2747–2754, 1998). As
an explanation for this phenomenon, we noted substantial formation of
SN-38 from CPT-11 and NPC by plasma CE, consistent with the low
circulating levels of NPC observed. In addition, transport studies in
Caco-2 monolayers indicated that nonglucuronidated SN-38 could cross
the membrane from apical to basolateral, indicating the potential for
recirculation processes that can prolong circulation times.
Interestingly, individual levels of fecal β-glucuronidase, which is
known to mediate SN-38G hydrolysis, were not related to any of the
SN-38 kinetic parameters ( r = 0.09;
P = 0.26), suggesting that interindividual
variation in this enzyme is unimportant in explaining SN-38
pharmacokinetic variability. We have also found, in contrast to earlier
data, that SN-38G/SN-38 plasma concentration ratios decrease over time
from ∼7 (up to 50 h) to ∼1 (at 500 h). This decrease
could be explained by the fact that glucuronidation of SN-38 and
bilirubin is increasingly competitive at lower drug levels. In
addition, no evidence was found for SN-38G transport through the Caco-2
cells. Our findings indicate that until now the circulation time of
SN-38 has been underestimated. This is of crucial importance to our
understanding of the clinical action of CPT-11 and for future
pharmacokinetic/pharmacodynamic relationships.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>10999728</pmid><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1078-0432 |
| ispartof | Clinical cancer research, 2000-09, Vol.6 (9), p.3451-3458 |
| issn | 1078-0432 1557-3265 |
| language | eng |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adult Aged Antineoplastic agents Antineoplastic Agents, Phytogenic - blood Antineoplastic Agents, Phytogenic - pharmacokinetics Biological and medical sciences Biotransformation Caco-2 Cells - metabolism Camptothecin - analogs & derivatives Camptothecin - blood Camptothecin - pharmacokinetics Carboxylic Ester Hydrolases - blood Chemotherapy Colorectal Neoplasms - blood Colorectal Neoplasms - drug therapy Colorectal Neoplasms - metabolism Feces - enzymology Female Glucuronidase - metabolism Half-Life Humans Male Medical sciences Middle Aged Oxidation-Reduction Pharmacology. Drug treatments |
| title | Factors Involved in Prolongation of the Terminal Disposition Phase of SN-38: Clinical and Experimental Studies |
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