Identification of metabolites of the novel anti-tumor drug candidate MDH-7 in rat urine by liquid chromatography coupled with triple quadrupole linear ion trap mass spectrometry
Rationale Our previous preliminary pharmacokinetic study demonstrated that the novel double pyrimidine tricyclic nucleoside MDH‐7 in rats had a very short half‐life (
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| Veröffentlicht in: | Rapid communications in mass spectrometry 2016-04, Vol.30 (7), p.1001-1010 |
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| creator | Li, Juan Chen, Yu Diao, Yanyan Su, Yingqian Wang, Qingli Yao, Zhicun Yi, Tianxiang Jin, Wenting Zhao, Dan Wang, Caihong Liu, Mengru Liu, Hongmin |
| description | Rationale
Our previous preliminary pharmacokinetic study demonstrated that the novel double pyrimidine tricyclic nucleoside MDH‐7 in rats had a very short half‐life ( |
| doi_str_mv | 10.1002/rcm.7506 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1800491388</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1773232032</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4206-9a8ac94b7e62dc1efedc7cf67aea59b8e92cf4892e634f31301d8536aa3fab3e3</originalsourceid><addsrcrecordid>eNqFkd9qFDEUh4Motq6CTyABb7yZmj8zyeRSV7utdBWlIngTMpkz3dSZyWySse5j-YZm6VpBEG9ycuA7H-fwQ-gpJSeUEPYy2OFEVkTcQ8eUKFkQxul9dExURYuSqvoIPYrxmhBKK0YeoiMmlFCqLI_Rz_MWxuQ6Z01yfsS-wwMk0_jeJYj7Nm0Aj_479NhksEjz4ANuw3yFrRlb15oEeP3mrJDYjTiYhOfgRsDNDvduO7sW203wg0n-Kphps8PWz1MPLb5xaYNTcLnB29lk4-Tzt8_DJuD9LikP4MHEiOMENmULpLB7jB50po_w5FAX6PPp28vlWXHxYXW-fHVR2JIRUShTG6vKRoJgraXQQWul7YQ0YCrV1KCY7cpaMRC87DjlhLZ1xYUxvDMNB75AL269U_DbGWLSg4sW-t6M4OeoaU1IqSiv6_-jUnLGGcnPAj3_C732cxjzIXuKVVRJQf4IbfAxBuj0FNxgwk5ToveJ65y43iee0WcH4dwM0N6BvyPOQHEL3Lgedv8U6U_L9UF44F1M8OOON-GbFpLLSn95v9If16eXX9-9FnrFfwFtRce1</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1772519760</pqid></control><display><type>article</type><title>Identification of metabolites of the novel anti-tumor drug candidate MDH-7 in rat urine by liquid chromatography coupled with triple quadrupole linear ion trap mass spectrometry</title><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><creator>Li, Juan ; Chen, Yu ; Diao, Yanyan ; Su, Yingqian ; Wang, Qingli ; Yao, Zhicun ; Yi, Tianxiang ; Jin, Wenting ; Zhao, Dan ; Wang, Caihong ; Liu, Mengru ; Liu, Hongmin</creator><creatorcontrib>Li, Juan ; Chen, Yu ; Diao, Yanyan ; Su, Yingqian ; Wang, Qingli ; Yao, Zhicun ; Yi, Tianxiang ; Jin, Wenting ; Zhao, Dan ; Wang, Caihong ; Liu, Mengru ; Liu, Hongmin</creatorcontrib><description>Rationale
Our previous preliminary pharmacokinetic study demonstrated that the novel double pyrimidine tricyclic nucleoside MDH‐7 in rats had a very short half‐life (<30 min) after oral administration. As a result, the in vivo metabolic profile of MDH‐7 should be investigated during early stages of drug development to better select drug candidates.
Methods
In this study, a rapid method was developed to identify the metabolites of MDH‐7 in rat urine by means of ultra‐performance liquid chromatography (UPLC) coupled with electrospray ionization mass spectrometry (ESI‐MS) using a triple quadrupole linear ion trap instrument. MDH‐7 and its metabolites were detected and characterized by the combined use of the multiple reaction monitoring–information‐dependent acquisition–enhanced product ion (MRM‐IDA‐EPI) mode and the precursor scan information–dependent acquisition–enhanced product ion (PREC‐IDA‐EPI) mode.
Results
Ten novel metabolites of MDH‐7 were identified and characterized in rat urine by LC/ESI‐MS and collision‐induced dissociation tandem mass spectrometry (CID‐MS/MS) analyses. M1 was identified as 5‐fluoro‐N4‐[(pentyloxy)carbonyl]cytosine; M2 and M3 were formed by hydroxylation products of M1. Metabolites M4–M10 were formed by a series of degradation reactions such as: deacetylation, hydroxylation, loss of the defluorocytosine base, oxidative‐deamination, loss of the defluorouracil base, N‐dealkylation and amide hydrolysis.
Conclusions
Based on the profiles of the metabolites, possible metabolic pathways of MDH‐7 in rats were proposed for the first time. This study provides new and available information on the metabolism of MDH‐7 which is very useful to further understand its in vivo metabolic fate. Copyright © 2016 John Wiley & Sons, Ltd.</description><identifier>ISSN: 0951-4198</identifier><identifier>EISSN: 1097-0231</identifier><identifier>DOI: 10.1002/rcm.7506</identifier><identifier>PMID: 26969944</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Animals ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - metabolism ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - urine ; Chromatography, Liquid - methods ; Drugs ; Hydroxylation ; In vivo methods and tests ; Liquid chromatography ; Male ; Mass spectrometry ; Metabolites ; Quadrupoles ; Rats ; Rats, Sprague-Dawley ; Tandem Mass Spectrometry - methods ; Urine</subject><ispartof>Rapid communications in mass spectrometry, 2016-04, Vol.30 (7), p.1001-1010</ispartof><rights>Copyright © 2016 John Wiley & Sons, Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4206-9a8ac94b7e62dc1efedc7cf67aea59b8e92cf4892e634f31301d8536aa3fab3e3</citedby><cites>FETCH-LOGICAL-c4206-9a8ac94b7e62dc1efedc7cf67aea59b8e92cf4892e634f31301d8536aa3fab3e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Frcm.7506$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Frcm.7506$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26969944$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Juan</creatorcontrib><creatorcontrib>Chen, Yu</creatorcontrib><creatorcontrib>Diao, Yanyan</creatorcontrib><creatorcontrib>Su, Yingqian</creatorcontrib><creatorcontrib>Wang, Qingli</creatorcontrib><creatorcontrib>Yao, Zhicun</creatorcontrib><creatorcontrib>Yi, Tianxiang</creatorcontrib><creatorcontrib>Jin, Wenting</creatorcontrib><creatorcontrib>Zhao, Dan</creatorcontrib><creatorcontrib>Wang, Caihong</creatorcontrib><creatorcontrib>Liu, Mengru</creatorcontrib><creatorcontrib>Liu, Hongmin</creatorcontrib><title>Identification of metabolites of the novel anti-tumor drug candidate MDH-7 in rat urine by liquid chromatography coupled with triple quadrupole linear ion trap mass spectrometry</title><title>Rapid communications in mass spectrometry</title><addtitle>Rapid Commun. Mass Spectrom</addtitle><description>Rationale
Our previous preliminary pharmacokinetic study demonstrated that the novel double pyrimidine tricyclic nucleoside MDH‐7 in rats had a very short half‐life (<30 min) after oral administration. As a result, the in vivo metabolic profile of MDH‐7 should be investigated during early stages of drug development to better select drug candidates.
Methods
In this study, a rapid method was developed to identify the metabolites of MDH‐7 in rat urine by means of ultra‐performance liquid chromatography (UPLC) coupled with electrospray ionization mass spectrometry (ESI‐MS) using a triple quadrupole linear ion trap instrument. MDH‐7 and its metabolites were detected and characterized by the combined use of the multiple reaction monitoring–information‐dependent acquisition–enhanced product ion (MRM‐IDA‐EPI) mode and the precursor scan information–dependent acquisition–enhanced product ion (PREC‐IDA‐EPI) mode.
Results
Ten novel metabolites of MDH‐7 were identified and characterized in rat urine by LC/ESI‐MS and collision‐induced dissociation tandem mass spectrometry (CID‐MS/MS) analyses. M1 was identified as 5‐fluoro‐N4‐[(pentyloxy)carbonyl]cytosine; M2 and M3 were formed by hydroxylation products of M1. Metabolites M4–M10 were formed by a series of degradation reactions such as: deacetylation, hydroxylation, loss of the defluorocytosine base, oxidative‐deamination, loss of the defluorouracil base, N‐dealkylation and amide hydrolysis.
Conclusions
Based on the profiles of the metabolites, possible metabolic pathways of MDH‐7 in rats were proposed for the first time. This study provides new and available information on the metabolism of MDH‐7 which is very useful to further understand its in vivo metabolic fate. Copyright © 2016 John Wiley & Sons, Ltd.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - metabolism</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - urine</subject><subject>Chromatography, Liquid - methods</subject><subject>Drugs</subject><subject>Hydroxylation</subject><subject>In vivo methods and tests</subject><subject>Liquid chromatography</subject><subject>Male</subject><subject>Mass spectrometry</subject><subject>Metabolites</subject><subject>Quadrupoles</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Tandem Mass Spectrometry - methods</subject><subject>Urine</subject><issn>0951-4198</issn><issn>1097-0231</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkd9qFDEUh4Motq6CTyABb7yZmj8zyeRSV7utdBWlIngTMpkz3dSZyWySse5j-YZm6VpBEG9ycuA7H-fwQ-gpJSeUEPYy2OFEVkTcQ8eUKFkQxul9dExURYuSqvoIPYrxmhBKK0YeoiMmlFCqLI_Rz_MWxuQ6Z01yfsS-wwMk0_jeJYj7Nm0Aj_479NhksEjz4ANuw3yFrRlb15oEeP3mrJDYjTiYhOfgRsDNDvduO7sW203wg0n-Kphps8PWz1MPLb5xaYNTcLnB29lk4-Tzt8_DJuD9LikP4MHEiOMENmULpLB7jB50po_w5FAX6PPp28vlWXHxYXW-fHVR2JIRUShTG6vKRoJgraXQQWul7YQ0YCrV1KCY7cpaMRC87DjlhLZ1xYUxvDMNB75AL269U_DbGWLSg4sW-t6M4OeoaU1IqSiv6_-jUnLGGcnPAj3_C732cxjzIXuKVVRJQf4IbfAxBuj0FNxgwk5ToveJ65y43iee0WcH4dwM0N6BvyPOQHEL3Lgedv8U6U_L9UF44F1M8OOON-GbFpLLSn95v9If16eXX9-9FnrFfwFtRce1</recordid><startdate>20160415</startdate><enddate>20160415</enddate><creator>Li, Juan</creator><creator>Chen, Yu</creator><creator>Diao, Yanyan</creator><creator>Su, Yingqian</creator><creator>Wang, Qingli</creator><creator>Yao, Zhicun</creator><creator>Yi, Tianxiang</creator><creator>Jin, Wenting</creator><creator>Zhao, Dan</creator><creator>Wang, Caihong</creator><creator>Liu, Mengru</creator><creator>Liu, Hongmin</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</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>7SR</scope><scope>7U5</scope><scope>8BQ</scope><scope>8FD</scope><scope>JG9</scope><scope>JQ2</scope><scope>L7M</scope><scope>7X8</scope></search><sort><creationdate>20160415</creationdate><title>Identification of metabolites of the novel anti-tumor drug candidate MDH-7 in rat urine by liquid chromatography coupled with triple quadrupole linear ion trap mass spectrometry</title><author>Li, Juan ; Chen, Yu ; Diao, Yanyan ; Su, Yingqian ; Wang, Qingli ; Yao, Zhicun ; Yi, Tianxiang ; Jin, Wenting ; Zhao, Dan ; Wang, Caihong ; Liu, Mengru ; Liu, Hongmin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4206-9a8ac94b7e62dc1efedc7cf67aea59b8e92cf4892e634f31301d8536aa3fab3e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - metabolism</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - urine</topic><topic>Chromatography, Liquid - methods</topic><topic>Drugs</topic><topic>Hydroxylation</topic><topic>In vivo methods and tests</topic><topic>Liquid chromatography</topic><topic>Male</topic><topic>Mass spectrometry</topic><topic>Metabolites</topic><topic>Quadrupoles</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Tandem Mass Spectrometry - methods</topic><topic>Urine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Juan</creatorcontrib><creatorcontrib>Chen, Yu</creatorcontrib><creatorcontrib>Diao, Yanyan</creatorcontrib><creatorcontrib>Su, Yingqian</creatorcontrib><creatorcontrib>Wang, Qingli</creatorcontrib><creatorcontrib>Yao, Zhicun</creatorcontrib><creatorcontrib>Yi, Tianxiang</creatorcontrib><creatorcontrib>Jin, Wenting</creatorcontrib><creatorcontrib>Zhao, Dan</creatorcontrib><creatorcontrib>Wang, Caihong</creatorcontrib><creatorcontrib>Liu, Mengru</creatorcontrib><creatorcontrib>Liu, Hongmin</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Engineered Materials Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>MEDLINE - Academic</collection><jtitle>Rapid communications in mass spectrometry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Juan</au><au>Chen, Yu</au><au>Diao, Yanyan</au><au>Su, Yingqian</au><au>Wang, Qingli</au><au>Yao, Zhicun</au><au>Yi, Tianxiang</au><au>Jin, Wenting</au><au>Zhao, Dan</au><au>Wang, Caihong</au><au>Liu, Mengru</au><au>Liu, Hongmin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of metabolites of the novel anti-tumor drug candidate MDH-7 in rat urine by liquid chromatography coupled with triple quadrupole linear ion trap mass spectrometry</atitle><jtitle>Rapid communications in mass spectrometry</jtitle><addtitle>Rapid Commun. Mass Spectrom</addtitle><date>2016-04-15</date><risdate>2016</risdate><volume>30</volume><issue>7</issue><spage>1001</spage><epage>1010</epage><pages>1001-1010</pages><issn>0951-4198</issn><eissn>1097-0231</eissn><abstract>Rationale
Our previous preliminary pharmacokinetic study demonstrated that the novel double pyrimidine tricyclic nucleoside MDH‐7 in rats had a very short half‐life (<30 min) after oral administration. As a result, the in vivo metabolic profile of MDH‐7 should be investigated during early stages of drug development to better select drug candidates.
Methods
In this study, a rapid method was developed to identify the metabolites of MDH‐7 in rat urine by means of ultra‐performance liquid chromatography (UPLC) coupled with electrospray ionization mass spectrometry (ESI‐MS) using a triple quadrupole linear ion trap instrument. MDH‐7 and its metabolites were detected and characterized by the combined use of the multiple reaction monitoring–information‐dependent acquisition–enhanced product ion (MRM‐IDA‐EPI) mode and the precursor scan information–dependent acquisition–enhanced product ion (PREC‐IDA‐EPI) mode.
Results
Ten novel metabolites of MDH‐7 were identified and characterized in rat urine by LC/ESI‐MS and collision‐induced dissociation tandem mass spectrometry (CID‐MS/MS) analyses. M1 was identified as 5‐fluoro‐N4‐[(pentyloxy)carbonyl]cytosine; M2 and M3 were formed by hydroxylation products of M1. Metabolites M4–M10 were formed by a series of degradation reactions such as: deacetylation, hydroxylation, loss of the defluorocytosine base, oxidative‐deamination, loss of the defluorouracil base, N‐dealkylation and amide hydrolysis.
Conclusions
Based on the profiles of the metabolites, possible metabolic pathways of MDH‐7 in rats were proposed for the first time. This study provides new and available information on the metabolism of MDH‐7 which is very useful to further understand its in vivo metabolic fate. Copyright © 2016 John Wiley & Sons, Ltd.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>26969944</pmid><doi>10.1002/rcm.7506</doi><tpages>10</tpages></addata></record> |
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| subjects | Animals Antineoplastic Agents - chemistry Antineoplastic Agents - metabolism Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - urine Chromatography, Liquid - methods Drugs Hydroxylation In vivo methods and tests Liquid chromatography Male Mass spectrometry Metabolites Quadrupoles Rats Rats, Sprague-Dawley Tandem Mass Spectrometry - methods Urine |
| title | Identification of metabolites of the novel anti-tumor drug candidate MDH-7 in rat urine by liquid chromatography coupled with triple quadrupole linear ion trap mass spectrometry |
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