A novel intravenous vehicle for preclinical cardiovascular screening of small molecule drug candidates in rat
Screening novel, poorly soluble small-molecule candidates for cardiovascular liabilities represents a key challenge in early drug discovery. This report describes a novel vehicle composed of 20% N,N-Dimethylacetamide (DMA)/40% Propylene glycol (PG)/40% Polyethylene Glycol (PEG-400) (DPP) for adminis...
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Veröffentlicht in: | Journal of pharmacological and toxicological methods 2016-11, Vol.82, p.62-67 |
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description | Screening novel, poorly soluble small-molecule candidates for cardiovascular liabilities represents a key challenge in early drug discovery. This report describes a novel vehicle composed of 20% N,N-Dimethylacetamide (DMA)/40% Propylene glycol (PG)/40% Polyethylene Glycol (PEG-400) (DPP) for administration of new chemical entities (NCEs) by slow intravenous (i.v.) infusion in a preclinical anesthetized rat model. The vehicle was designed considering both available excipient safety information and solubilization potential for poorly soluble NCEs. DPP solubilized 11 drugs, 8 of which were insoluble in 5% dextrose in water (D5W), and 5 insoluble in PEG-400 to a target concentration of 30mg/mL. DPP elicits no adverse cardiovascular responses in the anesthetized rat model despite containing 40% PEG-400, a commonly used organic solvent which elicits hypertension and bradycardia that often confounds interpretation of drug effects. Three compounds demonstrating adequate solubility in both DPP and D5W were screened in the anesthetized rat model. When normalized to plasma exposure, atenolol, sotalol and enalaprilat exhibited comparable mean arterial pressure, heart rate, and cardiac contractility responses regardless of formulation. While the antihypertensive effect of nifedipine was evident with both DPP and PEG-400 formulations, pressor effects from PEG-400 confounded interpretation of the magnitude of nifedipine's response. Plasma concentrations of atenolol and enalaprilat were greater in D5W formulation whereas sotalol exposures were greater when using DPP as a vehicle. These results demonstrate the utility of DPP as an intravenous vehicle for formulating poorly soluble compounds in early preclinical screening for cardiovascular safety studies. |
doi_str_mv | 10.1016/j.vascn.2016.07.002 |
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This report describes a novel vehicle composed of 20% N,N-Dimethylacetamide (DMA)/40% Propylene glycol (PG)/40% Polyethylene Glycol (PEG-400) (DPP) for administration of new chemical entities (NCEs) by slow intravenous (i.v.) infusion in a preclinical anesthetized rat model. The vehicle was designed considering both available excipient safety information and solubilization potential for poorly soluble NCEs. DPP solubilized 11 drugs, 8 of which were insoluble in 5% dextrose in water (D5W), and 5 insoluble in PEG-400 to a target concentration of 30mg/mL. DPP elicits no adverse cardiovascular responses in the anesthetized rat model despite containing 40% PEG-400, a commonly used organic solvent which elicits hypertension and bradycardia that often confounds interpretation of drug effects. Three compounds demonstrating adequate solubility in both DPP and D5W were screened in the anesthetized rat model. When normalized to plasma exposure, atenolol, sotalol and enalaprilat exhibited comparable mean arterial pressure, heart rate, and cardiac contractility responses regardless of formulation. While the antihypertensive effect of nifedipine was evident with both DPP and PEG-400 formulations, pressor effects from PEG-400 confounded interpretation of the magnitude of nifedipine's response. Plasma concentrations of atenolol and enalaprilat were greater in D5W formulation whereas sotalol exposures were greater when using DPP as a vehicle. These results demonstrate the utility of DPP as an intravenous vehicle for formulating poorly soluble compounds in early preclinical screening for cardiovascular safety studies.</description><identifier>ISSN: 1056-8719</identifier><identifier>EISSN: 1873-488X</identifier><identifier>DOI: 10.1016/j.vascn.2016.07.002</identifier><identifier>PMID: 27432021</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject><![CDATA[Acetamides - administration & dosage ; Acetamides - chemistry ; Acetamides - toxicity ; Animals ; Blood pressure ; Cardiac contractility ; Cardiovascular screening ; Drug Carriers - administration & dosage ; Drug Carriers - chemistry ; Drug Carriers - toxicity ; Drug Discovery - methods ; Drug Evaluation, Preclinical ; Excipients - administration & dosage ; Excipients - chemistry ; Excipients - toxicity ; Formulation ; Heart rate ; Hemodynamics - drug effects ; Infusions, Intravenous ; Lethal Dose 50 ; Male ; Methods ; Models, Cardiovascular ; Pharmaceutical Preparations - administration & dosage ; Pharmaceutical Preparations - blood ; Pharmaceutical Preparations - chemistry ; Pharmacokinetic ; Polyethylene Glycols - administration & dosage ; Polyethylene Glycols - chemistry ; Polyethylene Glycols - toxicity ; Propylene Glycol - administration & dosage ; Propylene Glycol - chemistry ; Propylene Glycol - toxicity ; Rats, Sprague-Dawley ; Safety pharmacology ; Small Molecule Libraries - administration & dosage ; Small Molecule Libraries - adverse effects ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - pharmacokinetics ; Solubility ; Vehicle]]></subject><ispartof>Journal of pharmacological and toxicological methods, 2016-11, Vol.82, p.62-67</ispartof><rights>2016 Elsevier Inc.</rights><rights>Copyright © 2016 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c359t-b7eb0c553830d297a0c46d2e0acff797346056c8eb392fbb40d7b96ad224453a3</citedby><cites>FETCH-LOGICAL-c359t-b7eb0c553830d297a0c46d2e0acff797346056c8eb392fbb40d7b96ad224453a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.vascn.2016.07.002$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27432021$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Banfor, Patricia N.</creatorcontrib><creatorcontrib>Gintant, Gary A.</creatorcontrib><creatorcontrib>Lipari, John M.</creatorcontrib><creatorcontrib>Zocharski, Philip D.</creatorcontrib><title>A novel intravenous vehicle for preclinical cardiovascular screening of small molecule drug candidates in rat</title><title>Journal of pharmacological and toxicological methods</title><addtitle>J Pharmacol Toxicol Methods</addtitle><description>Screening novel, poorly soluble small-molecule candidates for cardiovascular liabilities represents a key challenge in early drug discovery. This report describes a novel vehicle composed of 20% N,N-Dimethylacetamide (DMA)/40% Propylene glycol (PG)/40% Polyethylene Glycol (PEG-400) (DPP) for administration of new chemical entities (NCEs) by slow intravenous (i.v.) infusion in a preclinical anesthetized rat model. The vehicle was designed considering both available excipient safety information and solubilization potential for poorly soluble NCEs. DPP solubilized 11 drugs, 8 of which were insoluble in 5% dextrose in water (D5W), and 5 insoluble in PEG-400 to a target concentration of 30mg/mL. DPP elicits no adverse cardiovascular responses in the anesthetized rat model despite containing 40% PEG-400, a commonly used organic solvent which elicits hypertension and bradycardia that often confounds interpretation of drug effects. Three compounds demonstrating adequate solubility in both DPP and D5W were screened in the anesthetized rat model. When normalized to plasma exposure, atenolol, sotalol and enalaprilat exhibited comparable mean arterial pressure, heart rate, and cardiac contractility responses regardless of formulation. While the antihypertensive effect of nifedipine was evident with both DPP and PEG-400 formulations, pressor effects from PEG-400 confounded interpretation of the magnitude of nifedipine's response. Plasma concentrations of atenolol and enalaprilat were greater in D5W formulation whereas sotalol exposures were greater when using DPP as a vehicle. These results demonstrate the utility of DPP as an intravenous vehicle for formulating poorly soluble compounds in early preclinical screening for cardiovascular safety studies.</description><subject>Acetamides - administration & dosage</subject><subject>Acetamides - chemistry</subject><subject>Acetamides - toxicity</subject><subject>Animals</subject><subject>Blood pressure</subject><subject>Cardiac contractility</subject><subject>Cardiovascular screening</subject><subject>Drug Carriers - administration & dosage</subject><subject>Drug Carriers - chemistry</subject><subject>Drug Carriers - toxicity</subject><subject>Drug Discovery - methods</subject><subject>Drug Evaluation, Preclinical</subject><subject>Excipients - administration & dosage</subject><subject>Excipients - chemistry</subject><subject>Excipients - toxicity</subject><subject>Formulation</subject><subject>Heart rate</subject><subject>Hemodynamics - drug effects</subject><subject>Infusions, Intravenous</subject><subject>Lethal Dose 50</subject><subject>Male</subject><subject>Methods</subject><subject>Models, Cardiovascular</subject><subject>Pharmaceutical Preparations - administration & dosage</subject><subject>Pharmaceutical Preparations - blood</subject><subject>Pharmaceutical Preparations - chemistry</subject><subject>Pharmacokinetic</subject><subject>Polyethylene Glycols - administration & dosage</subject><subject>Polyethylene Glycols - chemistry</subject><subject>Polyethylene Glycols - toxicity</subject><subject>Propylene Glycol - administration & dosage</subject><subject>Propylene Glycol - chemistry</subject><subject>Propylene Glycol - toxicity</subject><subject>Rats, Sprague-Dawley</subject><subject>Safety pharmacology</subject><subject>Small Molecule Libraries - administration & dosage</subject><subject>Small Molecule Libraries - adverse effects</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - pharmacokinetics</subject><subject>Solubility</subject><subject>Vehicle</subject><issn>1056-8719</issn><issn>1873-488X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1u3CAURlHVqvl9gkoVy2zsXsA29iKLKErbSCN100rdIQzXKSMME7At9e3LdNIsuwLEuffTdwj5wKBmwLpP-3rT2YSal0cNsgbgb8g566Womr7_-bbcoe2qXrLhjFzkvAcAMbDmPTnjshEcODsn8x0NcUNPXViS3jDENdMNfznjkU4x0UNC411wRntqdLIuHlNXrxPNJiEGF55onGietfd0jh7LJ1Kb1qfCB-usXjCX9TTp5Yq8m7TPeP1yXpIfnx--33-tdt--PN7f7Soj2mGpRokjmLYVvQDLB6nBNJ3lCNpMkxykaLrSzPQ4ioFP49iAlePQact507RCi0tyc9p7SPF5xbyo2WWD3uuApaBiPe8k7wfGCipOqEkx54STOiQ36_RbMVBHz2qv_npWR88KpCqey9THl4B1nNG-zvwTW4DbE4Cl5uYwqWwcBoPWFaGLstH9N-AP42ORgA</recordid><startdate>201611</startdate><enddate>201611</enddate><creator>Banfor, Patricia N.</creator><creator>Gintant, Gary A.</creator><creator>Lipari, John M.</creator><creator>Zocharski, Philip D.</creator><general>Elsevier Inc</general><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>201611</creationdate><title>A novel intravenous vehicle for preclinical cardiovascular screening of small molecule drug candidates in rat</title><author>Banfor, Patricia N. ; Gintant, Gary A. ; Lipari, John M. ; Zocharski, Philip D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c359t-b7eb0c553830d297a0c46d2e0acff797346056c8eb392fbb40d7b96ad224453a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Acetamides - administration & dosage</topic><topic>Acetamides - chemistry</topic><topic>Acetamides - toxicity</topic><topic>Animals</topic><topic>Blood pressure</topic><topic>Cardiac contractility</topic><topic>Cardiovascular screening</topic><topic>Drug Carriers - administration & dosage</topic><topic>Drug Carriers - chemistry</topic><topic>Drug Carriers - toxicity</topic><topic>Drug Discovery - methods</topic><topic>Drug Evaluation, Preclinical</topic><topic>Excipients - administration & dosage</topic><topic>Excipients - chemistry</topic><topic>Excipients - toxicity</topic><topic>Formulation</topic><topic>Heart rate</topic><topic>Hemodynamics - drug effects</topic><topic>Infusions, Intravenous</topic><topic>Lethal Dose 50</topic><topic>Male</topic><topic>Methods</topic><topic>Models, Cardiovascular</topic><topic>Pharmaceutical Preparations - administration & dosage</topic><topic>Pharmaceutical Preparations - blood</topic><topic>Pharmaceutical Preparations - chemistry</topic><topic>Pharmacokinetic</topic><topic>Polyethylene Glycols - administration & dosage</topic><topic>Polyethylene Glycols - chemistry</topic><topic>Polyethylene Glycols - toxicity</topic><topic>Propylene Glycol - administration & dosage</topic><topic>Propylene Glycol - chemistry</topic><topic>Propylene Glycol - toxicity</topic><topic>Rats, Sprague-Dawley</topic><topic>Safety pharmacology</topic><topic>Small Molecule Libraries - administration & dosage</topic><topic>Small Molecule Libraries - adverse effects</topic><topic>Small Molecule Libraries - chemistry</topic><topic>Small Molecule Libraries - pharmacokinetics</topic><topic>Solubility</topic><topic>Vehicle</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Banfor, Patricia N.</creatorcontrib><creatorcontrib>Gintant, Gary A.</creatorcontrib><creatorcontrib>Lipari, John M.</creatorcontrib><creatorcontrib>Zocharski, Philip D.</creatorcontrib><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 pharmacological and toxicological methods</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Banfor, Patricia N.</au><au>Gintant, Gary A.</au><au>Lipari, John M.</au><au>Zocharski, Philip D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel intravenous vehicle for preclinical cardiovascular screening of small molecule drug candidates in rat</atitle><jtitle>Journal of pharmacological and toxicological methods</jtitle><addtitle>J Pharmacol Toxicol Methods</addtitle><date>2016-11</date><risdate>2016</risdate><volume>82</volume><spage>62</spage><epage>67</epage><pages>62-67</pages><issn>1056-8719</issn><eissn>1873-488X</eissn><abstract>Screening novel, poorly soluble small-molecule candidates for cardiovascular liabilities represents a key challenge in early drug discovery. This report describes a novel vehicle composed of 20% N,N-Dimethylacetamide (DMA)/40% Propylene glycol (PG)/40% Polyethylene Glycol (PEG-400) (DPP) for administration of new chemical entities (NCEs) by slow intravenous (i.v.) infusion in a preclinical anesthetized rat model. The vehicle was designed considering both available excipient safety information and solubilization potential for poorly soluble NCEs. DPP solubilized 11 drugs, 8 of which were insoluble in 5% dextrose in water (D5W), and 5 insoluble in PEG-400 to a target concentration of 30mg/mL. DPP elicits no adverse cardiovascular responses in the anesthetized rat model despite containing 40% PEG-400, a commonly used organic solvent which elicits hypertension and bradycardia that often confounds interpretation of drug effects. Three compounds demonstrating adequate solubility in both DPP and D5W were screened in the anesthetized rat model. When normalized to plasma exposure, atenolol, sotalol and enalaprilat exhibited comparable mean arterial pressure, heart rate, and cardiac contractility responses regardless of formulation. While the antihypertensive effect of nifedipine was evident with both DPP and PEG-400 formulations, pressor effects from PEG-400 confounded interpretation of the magnitude of nifedipine's response. Plasma concentrations of atenolol and enalaprilat were greater in D5W formulation whereas sotalol exposures were greater when using DPP as a vehicle. These results demonstrate the utility of DPP as an intravenous vehicle for formulating poorly soluble compounds in early preclinical screening for cardiovascular safety studies.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>27432021</pmid><doi>10.1016/j.vascn.2016.07.002</doi><tpages>6</tpages></addata></record> |
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subjects | Acetamides - administration & dosage Acetamides - chemistry Acetamides - toxicity Animals Blood pressure Cardiac contractility Cardiovascular screening Drug Carriers - administration & dosage Drug Carriers - chemistry Drug Carriers - toxicity Drug Discovery - methods Drug Evaluation, Preclinical Excipients - administration & dosage Excipients - chemistry Excipients - toxicity Formulation Heart rate Hemodynamics - drug effects Infusions, Intravenous Lethal Dose 50 Male Methods Models, Cardiovascular Pharmaceutical Preparations - administration & dosage Pharmaceutical Preparations - blood Pharmaceutical Preparations - chemistry Pharmacokinetic Polyethylene Glycols - administration & dosage Polyethylene Glycols - chemistry Polyethylene Glycols - toxicity Propylene Glycol - administration & dosage Propylene Glycol - chemistry Propylene Glycol - toxicity Rats, Sprague-Dawley Safety pharmacology Small Molecule Libraries - administration & dosage Small Molecule Libraries - adverse effects Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacokinetics Solubility Vehicle |
title | A novel intravenous vehicle for preclinical cardiovascular screening of small molecule drug candidates in rat |
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