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Improved oral bioavailability in rats of SR13668, a novel anti-cancer agent
Purpose SR13668, a bis-indole with potent activity in vitro and in vivo against various cancers and promising cancer chemopreventive activity, was found to have very low oral bioavailability,
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| Published in: | Cancer chemotherapy and pharmacology 2011-05, Vol.67 (5), p.995-1006 |
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| container_end_page | 1006 |
| container_issue | 5 |
| container_start_page | 995 |
| container_title | Cancer chemotherapy and pharmacology |
| container_volume | 67 |
| creator | Green, Carol E. Swezey, Robert Bakke, James Shinn, Walter Furimsky, Anna Bejugam, Naveen Shankar, Gita N. Jong, Ling Kapetanovic, Izet M. |
| description | Purpose
SR13668, a bis-indole with potent activity in vitro and in vivo against various cancers and promising cancer chemopreventive activity, was found to have very low oral bioavailability, |
| doi_str_mv | 10.1007/s00280-010-1395-9 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3061244</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>863768521</sourcerecordid><originalsourceid>FETCH-LOGICAL-c530t-35499cb38a7ac270121b352cca69c13d28b39aac590afaa8afcaf630ea5e12813</originalsourceid><addsrcrecordid>eNqFkd9rFDEQx4NY7PX0D_BFgiC-uDrJZHeTl4IUa0sLgj-ew2wue6bsbc5k76D_vTnvbKsgPoUwn-_Md-bL2HMBbwVA-y4DSA0VCKgEmroyj9hMKJQVaIWP2QxQqapuQR2zk5xvAEAJxCfsWEIjUcp6xq4uV-sUt37BY6KBdyHSlsJAXRjCdMvDyBNNmceef_kssGn0G058LIKB0ziFytHofOK09OP0lB31NGT_7PDO2bfzD1_PLqrrTx8vz95fV65GmCqslTGuQ00tOdmCkKLDWjpHjXECF1J3aIhcbYB6Ik29o75B8FR7IbXAOTvd911vupVfuDK6eLfrFFaUbm2kYP-sjOG7XcatRWiEVKo0eH1okOKPjc-TXYXs_DDQ6OMmWyNRGCFN-19SN9g2upY7Uy__Im_iJo3lDjsIW61-QWIPuRRzTr6_My3A7iK1-0gt7P4lUmuK5sXDbe8UvzMswKsDQNnR0KcSScj3nBJKQllpzuSey6U0Ln26d_jv6T8B5Ui3Zg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>863378421</pqid></control><display><type>article</type><title>Improved oral bioavailability in rats of SR13668, a novel anti-cancer agent</title><source>Springer Link</source><creator>Green, Carol E. ; Swezey, Robert ; Bakke, James ; Shinn, Walter ; Furimsky, Anna ; Bejugam, Naveen ; Shankar, Gita N. ; Jong, Ling ; Kapetanovic, Izet M.</creator><creatorcontrib>Green, Carol E. ; Swezey, Robert ; Bakke, James ; Shinn, Walter ; Furimsky, Anna ; Bejugam, Naveen ; Shankar, Gita N. ; Jong, Ling ; Kapetanovic, Izet M.</creatorcontrib><description>Purpose
SR13668, a bis-indole with potent activity in vitro and in vivo against various cancers and promising cancer chemopreventive activity, was found to have very low oral bioavailability, <1%, in rats during pilot pharmacokinetic studies. The objective of these studies was to better understand the source of low oral exposure and to develop a formulation that could be used in preclinical development studies.
Methods
An automated screening system for determining solubility in lipid-based vehicles, singly and in combination, was used to identify formulations that might enhance absorption by improving solubility of SR13668, and these results were confirmed in vivo using Sprague–Dawley rats. Pharmacokinetics of SR13668 was then determined in male and female Sprague–Dawley rats administered 1 mg/kg iv, 1, 10, and 30 mg/kg po formulated in PEG400:Labrasol® (1:1 v/v). Blood was collected at time points through 24 h and the concentration of SR13668 determined using HPLC with UV and fluorescence detection.
Results
SR13668 was found to be resistant to plasma esterases in vitro and relatively stable to rat and human liver microsomal metabolism. SR13668 concentrates in tissues as indicated by significantly higher levels in lung compared to blood, blood concentrations ~2.5-fold higher than plasma levels, and apparent volume of distribution (V) of ~5 l/kg. A marked sex difference was observed in exposure to SR13668 with area under the curve (AUC) significantly higher and clearance (CL) lower for female compared to male rats, after both iv and oral administration. The oral bioavailability (F) of SR13668 was 25.4 ± 3.8 and 27.7 ± 3.9% (30 mg/kg), for males and females, respectively. A putative metabolite (M1), molecular weight of 445 in the negative ion mode (i.e., SR13668 + 16), was identified in blood samples from both the iv and po routes, as well as in vitro microsomal samples.
Conclusions
In summary, while SR13668 does undergo metabolism, probably by the liver, the oral bioavailability of SR13668 in rats was dramatically improved by the use of formulation that contained permeation enhancers and promoted better solubilization of the drug.</description><identifier>ISSN: 0344-5704</identifier><identifier>ISSN: 1432-0843</identifier><identifier>EISSN: 1432-0843</identifier><identifier>DOI: 10.1007/s00280-010-1395-9</identifier><identifier>PMID: 20623225</identifier><identifier>CODEN: CCPHDZ</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer-Verlag</publisher><subject>Administration, Oral ; Animals ; Antineoplastic agents ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - pharmacokinetics ; Biological and medical sciences ; Biological Availability ; Cancer Research ; Carbazoles - administration & dosage ; Carbazoles - pharmacokinetics ; Female ; Humans ; In Vitro Techniques ; Injections, Intravenous ; Male ; Medical sciences ; Medicine ; Medicine & Public Health ; Microsomes, Liver - metabolism ; Oncology ; Original Article ; Pharmacology. Drug treatments ; Pharmacology/Toxicology ; Pilot Projects ; Rats ; Rats, Sprague-Dawley ; Sex Factors ; Solubility</subject><ispartof>Cancer chemotherapy and pharmacology, 2011-05, Vol.67 (5), p.995-1006</ispartof><rights>Springer-Verlag 2010</rights><rights>2015 INIST-CNRS</rights><rights>Springer-Verlag 2011</rights><rights>Springer-Verlag 2010 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c530t-35499cb38a7ac270121b352cca69c13d28b39aac590afaa8afcaf630ea5e12813</citedby><cites>FETCH-LOGICAL-c530t-35499cb38a7ac270121b352cca69c13d28b39aac590afaa8afcaf630ea5e12813</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,778,782,883,27907,27908</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24142092$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20623225$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Green, Carol E.</creatorcontrib><creatorcontrib>Swezey, Robert</creatorcontrib><creatorcontrib>Bakke, James</creatorcontrib><creatorcontrib>Shinn, Walter</creatorcontrib><creatorcontrib>Furimsky, Anna</creatorcontrib><creatorcontrib>Bejugam, Naveen</creatorcontrib><creatorcontrib>Shankar, Gita N.</creatorcontrib><creatorcontrib>Jong, Ling</creatorcontrib><creatorcontrib>Kapetanovic, Izet M.</creatorcontrib><title>Improved oral bioavailability in rats of SR13668, a novel anti-cancer agent</title><title>Cancer chemotherapy and pharmacology</title><addtitle>Cancer Chemother Pharmacol</addtitle><addtitle>Cancer Chemother Pharmacol</addtitle><description>Purpose
SR13668, a bis-indole with potent activity in vitro and in vivo against various cancers and promising cancer chemopreventive activity, was found to have very low oral bioavailability, <1%, in rats during pilot pharmacokinetic studies. The objective of these studies was to better understand the source of low oral exposure and to develop a formulation that could be used in preclinical development studies.
Methods
An automated screening system for determining solubility in lipid-based vehicles, singly and in combination, was used to identify formulations that might enhance absorption by improving solubility of SR13668, and these results were confirmed in vivo using Sprague–Dawley rats. Pharmacokinetics of SR13668 was then determined in male and female Sprague–Dawley rats administered 1 mg/kg iv, 1, 10, and 30 mg/kg po formulated in PEG400:Labrasol® (1:1 v/v). Blood was collected at time points through 24 h and the concentration of SR13668 determined using HPLC with UV and fluorescence detection.
Results
SR13668 was found to be resistant to plasma esterases in vitro and relatively stable to rat and human liver microsomal metabolism. SR13668 concentrates in tissues as indicated by significantly higher levels in lung compared to blood, blood concentrations ~2.5-fold higher than plasma levels, and apparent volume of distribution (V) of ~5 l/kg. A marked sex difference was observed in exposure to SR13668 with area under the curve (AUC) significantly higher and clearance (CL) lower for female compared to male rats, after both iv and oral administration. The oral bioavailability (F) of SR13668 was 25.4 ± 3.8 and 27.7 ± 3.9% (30 mg/kg), for males and females, respectively. A putative metabolite (M1), molecular weight of 445 in the negative ion mode (i.e., SR13668 + 16), was identified in blood samples from both the iv and po routes, as well as in vitro microsomal samples.
Conclusions
In summary, while SR13668 does undergo metabolism, probably by the liver, the oral bioavailability of SR13668 in rats was dramatically improved by the use of formulation that contained permeation enhancers and promoted better solubilization of the drug.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Cancer Research</subject><subject>Carbazoles - administration & dosage</subject><subject>Carbazoles - pharmacokinetics</subject><subject>Female</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Injections, Intravenous</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Microsomes, Liver - metabolism</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Pharmacology. Drug treatments</subject><subject>Pharmacology/Toxicology</subject><subject>Pilot Projects</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Sex Factors</subject><subject>Solubility</subject><issn>0344-5704</issn><issn>1432-0843</issn><issn>1432-0843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><recordid>eNqFkd9rFDEQx4NY7PX0D_BFgiC-uDrJZHeTl4IUa0sLgj-ew2wue6bsbc5k76D_vTnvbKsgPoUwn-_Md-bL2HMBbwVA-y4DSA0VCKgEmroyj9hMKJQVaIWP2QxQqapuQR2zk5xvAEAJxCfsWEIjUcp6xq4uV-sUt37BY6KBdyHSlsJAXRjCdMvDyBNNmceef_kssGn0G058LIKB0ziFytHofOK09OP0lB31NGT_7PDO2bfzD1_PLqrrTx8vz95fV65GmCqslTGuQ00tOdmCkKLDWjpHjXECF1J3aIhcbYB6Ik29o75B8FR7IbXAOTvd911vupVfuDK6eLfrFFaUbm2kYP-sjOG7XcatRWiEVKo0eH1okOKPjc-TXYXs_DDQ6OMmWyNRGCFN-19SN9g2upY7Uy__Im_iJo3lDjsIW61-QWIPuRRzTr6_My3A7iK1-0gt7P4lUmuK5sXDbe8UvzMswKsDQNnR0KcSScj3nBJKQllpzuSey6U0Ln26d_jv6T8B5Ui3Zg</recordid><startdate>20110501</startdate><enddate>20110501</enddate><creator>Green, Carol E.</creator><creator>Swezey, Robert</creator><creator>Bakke, James</creator><creator>Shinn, Walter</creator><creator>Furimsky, Anna</creator><creator>Bejugam, Naveen</creator><creator>Shankar, Gita N.</creator><creator>Jong, Ling</creator><creator>Kapetanovic, Izet M.</creator><general>Springer-Verlag</general><general>Springer</general><general>Springer Nature B.V</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>3V.</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20110501</creationdate><title>Improved oral bioavailability in rats of SR13668, a novel anti-cancer agent</title><author>Green, Carol E. ; Swezey, Robert ; Bakke, James ; Shinn, Walter ; Furimsky, Anna ; Bejugam, Naveen ; Shankar, Gita N. ; Jong, Ling ; Kapetanovic, Izet M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c530t-35499cb38a7ac270121b352cca69c13d28b39aac590afaa8afcaf630ea5e12813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>Cancer Research</topic><topic>Carbazoles - administration & dosage</topic><topic>Carbazoles - pharmacokinetics</topic><topic>Female</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Injections, Intravenous</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Microsomes, Liver - metabolism</topic><topic>Oncology</topic><topic>Original Article</topic><topic>Pharmacology. Drug treatments</topic><topic>Pharmacology/Toxicology</topic><topic>Pilot Projects</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Sex Factors</topic><topic>Solubility</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Green, Carol E.</creatorcontrib><creatorcontrib>Swezey, Robert</creatorcontrib><creatorcontrib>Bakke, James</creatorcontrib><creatorcontrib>Shinn, Walter</creatorcontrib><creatorcontrib>Furimsky, Anna</creatorcontrib><creatorcontrib>Bejugam, Naveen</creatorcontrib><creatorcontrib>Shankar, Gita N.</creatorcontrib><creatorcontrib>Jong, Ling</creatorcontrib><creatorcontrib>Kapetanovic, Izet 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>ProQuest Central (Corporate)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer chemotherapy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Green, Carol E.</au><au>Swezey, Robert</au><au>Bakke, James</au><au>Shinn, Walter</au><au>Furimsky, Anna</au><au>Bejugam, Naveen</au><au>Shankar, Gita N.</au><au>Jong, Ling</au><au>Kapetanovic, Izet M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Improved oral bioavailability in rats of SR13668, a novel anti-cancer agent</atitle><jtitle>Cancer chemotherapy and pharmacology</jtitle><stitle>Cancer Chemother Pharmacol</stitle><addtitle>Cancer Chemother Pharmacol</addtitle><date>2011-05-01</date><risdate>2011</risdate><volume>67</volume><issue>5</issue><spage>995</spage><epage>1006</epage><pages>995-1006</pages><issn>0344-5704</issn><issn>1432-0843</issn><eissn>1432-0843</eissn><coden>CCPHDZ</coden><abstract>Purpose
SR13668, a bis-indole with potent activity in vitro and in vivo against various cancers and promising cancer chemopreventive activity, was found to have very low oral bioavailability, <1%, in rats during pilot pharmacokinetic studies. The objective of these studies was to better understand the source of low oral exposure and to develop a formulation that could be used in preclinical development studies.
Methods
An automated screening system for determining solubility in lipid-based vehicles, singly and in combination, was used to identify formulations that might enhance absorption by improving solubility of SR13668, and these results were confirmed in vivo using Sprague–Dawley rats. Pharmacokinetics of SR13668 was then determined in male and female Sprague–Dawley rats administered 1 mg/kg iv, 1, 10, and 30 mg/kg po formulated in PEG400:Labrasol® (1:1 v/v). Blood was collected at time points through 24 h and the concentration of SR13668 determined using HPLC with UV and fluorescence detection.
Results
SR13668 was found to be resistant to plasma esterases in vitro and relatively stable to rat and human liver microsomal metabolism. SR13668 concentrates in tissues as indicated by significantly higher levels in lung compared to blood, blood concentrations ~2.5-fold higher than plasma levels, and apparent volume of distribution (V) of ~5 l/kg. A marked sex difference was observed in exposure to SR13668 with area under the curve (AUC) significantly higher and clearance (CL) lower for female compared to male rats, after both iv and oral administration. The oral bioavailability (F) of SR13668 was 25.4 ± 3.8 and 27.7 ± 3.9% (30 mg/kg), for males and females, respectively. A putative metabolite (M1), molecular weight of 445 in the negative ion mode (i.e., SR13668 + 16), was identified in blood samples from both the iv and po routes, as well as in vitro microsomal samples.
Conclusions
In summary, while SR13668 does undergo metabolism, probably by the liver, the oral bioavailability of SR13668 in rats was dramatically improved by the use of formulation that contained permeation enhancers and promoted better solubilization of the drug.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer-Verlag</pub><pmid>20623225</pmid><doi>10.1007/s00280-010-1395-9</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0344-5704 |
| ispartof | Cancer chemotherapy and pharmacology, 2011-05, Vol.67 (5), p.995-1006 |
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| language | eng |
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| subjects | Administration, Oral Animals Antineoplastic agents Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacokinetics Biological and medical sciences Biological Availability Cancer Research Carbazoles - administration & dosage Carbazoles - pharmacokinetics Female Humans In Vitro Techniques Injections, Intravenous Male Medical sciences Medicine Medicine & Public Health Microsomes, Liver - metabolism Oncology Original Article Pharmacology. Drug treatments Pharmacology/Toxicology Pilot Projects Rats Rats, Sprague-Dawley Sex Factors Solubility |
| title | Improved oral bioavailability in rats of SR13668, a novel anti-cancer agent |
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