Preparation and Analysis of Deuterium-Labeled Aspirin: Application to Pharmacokinetic Studies
Inhibition of endogenous prostacyclin and thromboxane biosynthesis by aspirin is critically dose-dependent in humans. Gastrointestinal and hepatic hydrolysis may limit systemic availability of aspirin, especially in low doses, perhaps contributing to the biochemical selectivity of aspirin. Existing...
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| Veröffentlicht in: | J. Pharm. Sci.; (United States) 1985-02, Vol.74 (2), p.188-192 |
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| creator | Pedersen, Anders Kirstein Fitzgerald, Garret A. |
| description | Inhibition of endogenous prostacyclin and thromboxane biosynthesis by aspirin is critically dose-dependent in humans. Gastrointestinal and hepatic hydrolysis may limit systemic availability of aspirin, especially in low doses, perhaps contributing to the biochemical selectivity of aspirin. Existing analytical methods do not permit determination of systemic bioavailability when low ( |
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Gastrointestinal and hepatic hydrolysis may limit systemic availability of aspirin, especially in low doses, perhaps contributing to the biochemical selectivity of aspirin. Existing analytical methods do not permit determination of systemic bioavailability when low (<100 mg) doses of aspirin are administered. Deuterium-labeled aspirin (2-acetoxy[3,4,5,6-2H4]benzoic acid) was synthesized from salicylic acid by catalytic exchange and subsequent acetylation. Analysis of the compounds as benzyl esters by GC–MS followed extractive alkylation from plasma. Heptadeuterated compounds were used as internal standards. Simultaneous administration of tetradeuterated aspirin intravenously with native aspirin orally to anesthetized dogs permitted kinetic studies of both aspirin and salicylic acid. The sensitivity of the method is superior to published methods using HPLC and, thus, more applicable to studies of low dose aspirin. Pulse administration of stable isotope-labeled aspirin permits detailed and repeated studies of dose-related aspirin pharmacokinetics in humans.</description><identifier>ISSN: 0022-3549</identifier><identifier>EISSN: 1520-6017</identifier><identifier>DOI: 10.1002/jps.2600740217</identifier><identifier>PMID: 3989690</identifier><identifier>CODEN: JPMSAE</identifier><language>eng</language><publisher>Washington: Elsevier Inc</publisher><subject>400702 - Radiochemistry & Nuclear Chemistry- Properties of Radioactive Materials ; 551001 - Physiological Systems- Tracer Techniques ; ACETYLSALICYLIC ACID ; ANALGESICS ; ANIMALS ; ANTIPYRETICS ; Aspirin - blood ; Aspirin - metabolism ; BASIC BIOLOGICAL SCIENCES ; Biological and medical sciences ; BIOLOGICAL AVAILABILITY ; BIOSYNTHESIS ; CARBOXYLIC ACIDS ; CENTRAL NERVOUS SYSTEM DEPRESSANTS ; CHEMICAL PREPARATION ; Chromatography, High Pressure Liquid ; Deuterium ; DEUTERIUM COMPOUNDS ; DOGS ; DRUGS ; Gas Chromatography-Mass Spectrometry ; General pharmacology ; Humans ; HYDROGEN COMPOUNDS ; HYDROXY ACIDS ; Isotope Labeling - methods ; KINETICS ; Male ; MAMMALS ; Medical sciences ; ORGANIC ACIDS ; ORGANIC COMPOUNDS ; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions ; PHARMACOLOGY ; Pharmacology. Drug treatments ; RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY ; SYNTHESIS ; VERTEBRATES</subject><ispartof>J. Pharm. 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Pharm. Sci.; (United States)</title><addtitle>J. Pharm. Sci</addtitle><description>Inhibition of endogenous prostacyclin and thromboxane biosynthesis by aspirin is critically dose-dependent in humans. Gastrointestinal and hepatic hydrolysis may limit systemic availability of aspirin, especially in low doses, perhaps contributing to the biochemical selectivity of aspirin. Existing analytical methods do not permit determination of systemic bioavailability when low (<100 mg) doses of aspirin are administered. Deuterium-labeled aspirin (2-acetoxy[3,4,5,6-2H4]benzoic acid) was synthesized from salicylic acid by catalytic exchange and subsequent acetylation. Analysis of the compounds as benzyl esters by GC–MS followed extractive alkylation from plasma. Heptadeuterated compounds were used as internal standards. Simultaneous administration of tetradeuterated aspirin intravenously with native aspirin orally to anesthetized dogs permitted kinetic studies of both aspirin and salicylic acid. The sensitivity of the method is superior to published methods using HPLC and, thus, more applicable to studies of low dose aspirin. Pulse administration of stable isotope-labeled aspirin permits detailed and repeated studies of dose-related aspirin pharmacokinetics in humans.</description><subject>400702 - Radiochemistry & Nuclear Chemistry- Properties of Radioactive Materials</subject><subject>551001 - Physiological Systems- Tracer Techniques</subject><subject>ACETYLSALICYLIC ACID</subject><subject>ANALGESICS</subject><subject>ANIMALS</subject><subject>ANTIPYRETICS</subject><subject>Aspirin - blood</subject><subject>Aspirin - metabolism</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Biological and medical sciences</subject><subject>BIOLOGICAL AVAILABILITY</subject><subject>BIOSYNTHESIS</subject><subject>CARBOXYLIC ACIDS</subject><subject>CENTRAL NERVOUS SYSTEM DEPRESSANTS</subject><subject>CHEMICAL PREPARATION</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Deuterium</subject><subject>DEUTERIUM COMPOUNDS</subject><subject>DOGS</subject><subject>DRUGS</subject><subject>Gas Chromatography-Mass Spectrometry</subject><subject>General pharmacology</subject><subject>Humans</subject><subject>HYDROGEN COMPOUNDS</subject><subject>HYDROXY ACIDS</subject><subject>Isotope Labeling - methods</subject><subject>KINETICS</subject><subject>Male</subject><subject>MAMMALS</subject><subject>Medical sciences</subject><subject>ORGANIC ACIDS</subject><subject>ORGANIC COMPOUNDS</subject><subject>Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions</subject><subject>PHARMACOLOGY</subject><subject>Pharmacology. Drug treatments</subject><subject>RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY</subject><subject>SYNTHESIS</subject><subject>VERTEBRATES</subject><issn>0022-3549</issn><issn>1520-6017</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1985</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc-L1DAYhoMo67h69SYUEW8d86NpUm_DqqtSdWAVTxLS5Cub3U5Sk1ad_94MHUY8iKccvud9k-8JQo8JXhOM6YubMa1pjbGoMCXiDloRTnFZYyLuolUGaMl41dxHD1K6wRjXmPMzdMYa2dQNXqFv2wijjnpywRfa22Lj9bBPLhWhL17BPEF0865sdQcD5GkaXXT-ZbEZx8GZJTaFYnut406bcOs8TM4UV9NsHaSH6F6vhwSPjuc5-vLm9eeLt2X76fLdxaYtTSWZKLmwhhPWUamxpJZVlmpMMK0wE1proFAzkwnZN8I2tea9MU1XdxW3DZUE2Dl6uvSGNDmVjJvAXJvgPZhJcdxwSliGni_QGMP3GdKkdi4ZGAbtIcxJiRrLuuIyg-sFNDGkFKFXY3Q7HfeKYHWQrrJ09Ud6Djw5Ns_dDuwJP1rO82fHuU5GD33U3rh0wmRFWVUfapoF--kG2P_nUvV-e_XXE8ol69IEv05ZHW9VbhZcff14qT5sW9ESJlSVebnwkL_lh4N4sAbegHXxIM0G969tfwP-lrvh</recordid><startdate>198502</startdate><enddate>198502</enddate><creator>Pedersen, Anders Kirstein</creator><creator>Fitzgerald, Garret A.</creator><general>Elsevier Inc</general><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley</general><general>American Pharmaceutical Association</general><scope>BSCLL</scope><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>7X8</scope><scope>OTOTI</scope></search><sort><creationdate>198502</creationdate><title>Preparation and Analysis of Deuterium-Labeled Aspirin: Application to Pharmacokinetic Studies</title><author>Pedersen, Anders Kirstein ; Fitzgerald, Garret A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4837-57dc513b28a082d34d2a01024037aaae2e63cc518f97d96a5fcc9b6b45d9281e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1985</creationdate><topic>400702 - Radiochemistry & Nuclear Chemistry- Properties of Radioactive Materials</topic><topic>551001 - Physiological Systems- Tracer Techniques</topic><topic>ACETYLSALICYLIC ACID</topic><topic>ANALGESICS</topic><topic>ANIMALS</topic><topic>ANTIPYRETICS</topic><topic>Aspirin - blood</topic><topic>Aspirin - metabolism</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>Biological and medical sciences</topic><topic>BIOLOGICAL AVAILABILITY</topic><topic>BIOSYNTHESIS</topic><topic>CARBOXYLIC ACIDS</topic><topic>CENTRAL NERVOUS SYSTEM DEPRESSANTS</topic><topic>CHEMICAL PREPARATION</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Deuterium</topic><topic>DEUTERIUM COMPOUNDS</topic><topic>DOGS</topic><topic>DRUGS</topic><topic>Gas Chromatography-Mass Spectrometry</topic><topic>General pharmacology</topic><topic>Humans</topic><topic>HYDROGEN COMPOUNDS</topic><topic>HYDROXY ACIDS</topic><topic>Isotope Labeling - methods</topic><topic>KINETICS</topic><topic>Male</topic><topic>MAMMALS</topic><topic>Medical sciences</topic><topic>ORGANIC ACIDS</topic><topic>ORGANIC COMPOUNDS</topic><topic>Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions</topic><topic>PHARMACOLOGY</topic><topic>Pharmacology. Drug treatments</topic><topic>RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY</topic><topic>SYNTHESIS</topic><topic>VERTEBRATES</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pedersen, Anders Kirstein</creatorcontrib><creatorcontrib>Fitzgerald, Garret A.</creatorcontrib><creatorcontrib>Vanderbilt Univ., Nashville, TN</creatorcontrib><collection>Istex</collection><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>MEDLINE - Academic</collection><collection>OSTI.GOV</collection><jtitle>J. Pharm. Sci.; (United States)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pedersen, Anders Kirstein</au><au>Fitzgerald, Garret A.</au><aucorp>Vanderbilt Univ., Nashville, TN</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Preparation and Analysis of Deuterium-Labeled Aspirin: Application to Pharmacokinetic Studies</atitle><jtitle>J. Pharm. Sci.; (United States)</jtitle><addtitle>J. Pharm. Sci</addtitle><date>1985-02</date><risdate>1985</risdate><volume>74</volume><issue>2</issue><spage>188</spage><epage>192</epage><pages>188-192</pages><issn>0022-3549</issn><eissn>1520-6017</eissn><coden>JPMSAE</coden><abstract>Inhibition of endogenous prostacyclin and thromboxane biosynthesis by aspirin is critically dose-dependent in humans. Gastrointestinal and hepatic hydrolysis may limit systemic availability of aspirin, especially in low doses, perhaps contributing to the biochemical selectivity of aspirin. Existing analytical methods do not permit determination of systemic bioavailability when low (<100 mg) doses of aspirin are administered. Deuterium-labeled aspirin (2-acetoxy[3,4,5,6-2H4]benzoic acid) was synthesized from salicylic acid by catalytic exchange and subsequent acetylation. Analysis of the compounds as benzyl esters by GC–MS followed extractive alkylation from plasma. Heptadeuterated compounds were used as internal standards. Simultaneous administration of tetradeuterated aspirin intravenously with native aspirin orally to anesthetized dogs permitted kinetic studies of both aspirin and salicylic acid. The sensitivity of the method is superior to published methods using HPLC and, thus, more applicable to studies of low dose aspirin. Pulse administration of stable isotope-labeled aspirin permits detailed and repeated studies of dose-related aspirin pharmacokinetics in humans.</abstract><cop>Washington</cop><pub>Elsevier Inc</pub><pmid>3989690</pmid><doi>10.1002/jps.2600740217</doi><tpages>5</tpages></addata></record> |
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| ispartof | J. Pharm. Sci.; (United States), 1985-02, Vol.74 (2), p.188-192 |
| issn | 0022-3549 1520-6017 |
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| subjects | 400702 - Radiochemistry & Nuclear Chemistry- Properties of Radioactive Materials 551001 - Physiological Systems- Tracer Techniques ACETYLSALICYLIC ACID ANALGESICS ANIMALS ANTIPYRETICS Aspirin - blood Aspirin - metabolism BASIC BIOLOGICAL SCIENCES Biological and medical sciences BIOLOGICAL AVAILABILITY BIOSYNTHESIS CARBOXYLIC ACIDS CENTRAL NERVOUS SYSTEM DEPRESSANTS CHEMICAL PREPARATION Chromatography, High Pressure Liquid Deuterium DEUTERIUM COMPOUNDS DOGS DRUGS Gas Chromatography-Mass Spectrometry General pharmacology Humans HYDROGEN COMPOUNDS HYDROXY ACIDS Isotope Labeling - methods KINETICS Male MAMMALS Medical sciences ORGANIC ACIDS ORGANIC COMPOUNDS Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions PHARMACOLOGY Pharmacology. Drug treatments RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY SYNTHESIS VERTEBRATES |
| title | Preparation and Analysis of Deuterium-Labeled Aspirin: Application to Pharmacokinetic Studies |
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