Stereoselective disposition of hydroxychloroquine and its metabolites in rats
Identifieur interne : 000036 ( Istex/Corpus ); précédent : 000035; suivant : 000037Stereoselective disposition of hydroxychloroquine and its metabolites in rats
Auteurs : Yimin Wei ; Gloria A. Nygard ; Shari L. Ellertson ; Shoukry K. W. KhalilSource :
- Chirality [ 0899-0042 ] ; 1995.
Abstract
Racemic hydroxychloroquine‐sulfate (HCQ‐sulfate) was administered to rats orally. Groups of 9 male and 9 female rats received doses of 0, 8, 16, or 24 mg/kg/day for 6 weeks, followed by a reduction of the higher doses to 8 mg/kg/day for the duration of the study. Whole blood samples were collected at 0, 3, 6, 8, and 10 weeks, and eleven tissues were harvested after the tenth week. The concentrations and enantiomer ratios of the parent drug and three metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ), were determined. The highest concentration of HCQ was found in the intestinal smooth muscle, and the lowest in the brain and adipose tissue. The highest concentrations of the metabolites were found in the liver, adrenals, and lung tissue. The metabolism of HCQ in the rats was found to be stereoselective with R/S > 1 for the drug and < 1 for the metabolites. Gender‐specific differences in the proportions of the drug and its metabolites and their enantiomers in blood and tissue were found. Varying dosages appeared to have only a temporary influence on blood concentrations and not to effect the enantiomer ratios in blood. Only a limited number of tissues exhibited significant differences between dose groups. There were no observed differences in enantiomer ratios among the blood collection times. © 1995 Wiley‐Liss, Inc.
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DOI: 10.1002/chir.530070807
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Khalil</name><affiliation><mods:affiliation>Pharmacokinetic Drug Analysis Laboratory and Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, North Dakota</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence address: Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, ND 58105</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Chirality</title><title level="j" type="alt">CHIRALITY</title><idno type="ISSN">0899-0042</idno><idno type="eISSN">1520-636X</idno><imprint><biblScope unit="vol">7</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="598">598</biblScope><biblScope unit="page" to="604">604</biblScope><biblScope unit="page-count">7</biblScope><publisher>Alan R. Liss, Inc.</publisher><pubPlace>New York</pubPlace><date type="published" when="1995">1995</date></imprint><idno type="ISSN">0899-0042</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0899-0042</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Racemic hydroxychloroquine‐sulfate (HCQ‐sulfate) was administered to rats orally. Groups of 9 male and 9 female rats received doses of 0, 8, 16, or 24 mg/kg/day for 6 weeks, followed by a reduction of the higher doses to 8 mg/kg/day for the duration of the study. Whole blood samples were collected at 0, 3, 6, 8, and 10 weeks, and eleven tissues were harvested after the tenth week. The concentrations and enantiomer ratios of the parent drug and three metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ), were determined. The highest concentration of HCQ was found in the intestinal smooth muscle, and the lowest in the brain and adipose tissue. The highest concentrations of the metabolites were found in the liver, adrenals, and lung tissue. The metabolism of HCQ in the rats was found to be stereoselective with R/S > 1 for the drug and < 1 for the metabolites. Gender‐specific differences in the proportions of the drug and its metabolites and their enantiomers in blood and tissue were found. Varying dosages appeared to have only a temporary influence on blood concentrations and not to effect the enantiomer ratios in blood. Only a limited number of tissues exhibited significant differences between dose groups. 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Khalil</name><affiliations><json:string>Pharmacokinetic Drug Analysis Laboratory and Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, North Dakota</json:string><json:string>Correspondence address: Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, ND 58105</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>hydroxychloroquine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>metabolites</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>enantiomers</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>disposition</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>distribution</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>stereoselectivity</value></json:item></subject><articleId><json:string>CHIR530070807</json:string></articleId><arkIstex>ark:/67375/WNG-TPBSLQSD-R</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>Racemic hydroxychloroquine‐sulfate (HCQ‐sulfate) was administered to rats orally. Groups of 9 male and 9 female rats received doses of 0, 8, 16, or 24 mg/kg/day for 6 weeks, followed by a reduction of the higher doses to 8 mg/kg/day for the duration of the study. Whole blood samples were collected at 0, 3, 6, 8, and 10 weeks, and eleven tissues were harvested after the tenth week. The concentrations and enantiomer ratios of the parent drug and three metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ), were determined. The highest concentration of HCQ was found in the intestinal smooth muscle, and the lowest in the brain and adipose tissue. The highest concentrations of the metabolites were found in the liver, adrenals, and lung tissue. The metabolism of HCQ in the rats was found to be stereoselective with R/S > 1 for the drug and > 1 for the metabolites. Gender‐specific differences in the proportions of the drug and its metabolites and their enantiomers in blood and tissue were found. Varying dosages appeared to have only a temporary influence on blood concentrations and not to effect the enantiomer ratios in blood. Only a limited number of tissues exhibited significant differences between dose groups. 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The highest concentrations of the metabolites were found in the liver, adrenals, and lung tissue.</p><p>The metabolism of HCQ in the rats was found to be stereoselective with R/S > 1 for the drug and < 1 for the metabolites. Gender‐specific differences in the proportions of the drug and its metabolites and their enantiomers in blood and tissue were found. Varying dosages appeared to have only a temporary influence on blood concentrations and not to effect the enantiomer ratios in blood. Only a limited number of tissues exhibited significant differences between dose groups. There were no observed differences in enantiomer ratios among the blood collection times. © 1995 Wiley‐Liss, Inc.</p></abstract><textClass><keywords xml:lang="en"><term xml:id="kwd1">hydroxychloroquine</term><term xml:id="kwd2">metabolites</term><term xml:id="kwd3">enantiomers</term><term xml:id="kwd4">disposition</term><term xml:id="kwd5">distribution</term><term xml:id="kwd6">stereoselectivity</term></keywords><keywords rend="articleCategory"><term>Full Paper</term></keywords><keywords rend="tocHeading1"><term>Full Papers</term></keywords></textClass><langUsage><language ident="en"></language></langUsage></profileDesc><revisionDesc><change when="2019-12-20" who="#istex" xml:id="pub2tei">formatting</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/WNG-TPBSLQSD-R/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Alan R. Liss, Inc.</publisherName><publisherLoc>New York</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1520-636X</doi><issn type="print">0899-0042</issn><issn type="electronic">1520-636X</issn><idGroup><id type="product" value="CHIR"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="CHIRALITY">Chirality</title><title type="short">Chirality</title></titleGroup></publicationMeta><publicationMeta level="part" position="80"><doi origin="wiley" registered="yes">10.1002/chir.v7:8</doi><numberingGroup><numbering type="journalVolume" number="7">7</numbering><numbering type="journalIssue">8</numbering></numberingGroup><coverDate startDate="1995">1995</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="7" status="forIssue"><doi origin="wiley" registered="yes">10.1002/chir.530070807</doi><idGroup><id type="unit" value="CHIR530070807"></id></idGroup><countGroup><count type="pageTotal" number="7"></count></countGroup><titleGroup><title type="articleCategory">Full Paper</title><title type="tocHeading1">Full Papers</title></titleGroup><copyright ownership="publisher">Copyright © 1995 Wiley‐Liss, Inc.</copyright><eventGroup><event type="manuscriptReceived" date="1995-04-13"></event><event type="manuscriptAccepted" date="1995-07-17"></event><event type="firstOnline" date="2004-09-17"></event><event type="publishedOnlineFinalForm" date="2004-09-17"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.3.2 mode:FullText source:HeaderRef result:HeaderRef" date="2010-03-09"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-09"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-17"></event></eventGroup><numberingGroup><numbering type="pageFirst">598</numbering><numbering type="pageLast">604</numbering></numberingGroup><correspondenceTo>Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, ND 58105</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:CHIR.CHIR530070807.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="2"></count><count type="tableTotal" number="4"></count><count type="referenceTotal" number="24"></count></countGroup><titleGroup><title type="main" xml:lang="en">Stereoselective disposition of hydroxychloroquine and its metabolites in rats</title><title type="short" xml:lang="en">STEREOSELECTIVE DISPOSITION OF HCQ IN RATS</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Yimin</givenNames><familyName>Wei</familyName></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Gloria A.</givenNames><familyName>Nygard</familyName></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Shari L.</givenNames><familyName>Ellertson</familyName></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af1" corresponding="yes"><personName><givenNames>Shoukry K.W.</givenNames><familyName>Khalil</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="US" type="organization"><unparsedAffiliation>Pharmacokinetic Drug Analysis Laboratory and Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, North Dakota</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">hydroxychloroquine</keyword><keyword xml:id="kwd2">metabolites</keyword><keyword xml:id="kwd3">enantiomers</keyword><keyword xml:id="kwd4">disposition</keyword><keyword xml:id="kwd5">distribution</keyword><keyword xml:id="kwd6">stereoselectivity</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Racemic hydroxychloroquine‐sulfate (HCQ‐sulfate) was administered to rats orally. Groups of 9 male and 9 female rats received doses of 0, 8, 16, or 24 mg/kg/day for 6 weeks, followed by a reduction of the higher doses to 8 mg/kg/day for the duration of the study. Whole blood samples were collected at 0, 3, 6, 8, and 10 weeks, and eleven tissues were harvested after the tenth week. The concentrations and enantiomer ratios of the parent drug and three metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ), were determined. The highest concentration of HCQ was found in the intestinal smooth muscle, and the lowest in the brain and adipose tissue. The highest concentrations of the metabolites were found in the liver, adrenals, and lung tissue.</p><p>The metabolism of HCQ in the rats was found to be stereoselective with R/S > 1 for the drug and < 1 for the metabolites. Gender‐specific differences in the proportions of the drug and its metabolites and their enantiomers in blood and tissue were found. Varying dosages appeared to have only a temporary influence on blood concentrations and not to effect the enantiomer ratios in blood. Only a limited number of tissues exhibited significant differences between dose groups. There were no observed differences in enantiomer ratios among the blood collection times. © 1995 Wiley‐Liss, Inc.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Stereoselective disposition of hydroxychloroquine and its metabolites in rats</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>STEREOSELECTIVE DISPOSITION OF HCQ IN RATS</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Stereoselective disposition of hydroxychloroquine and its metabolites in rats</title></titleInfo><name type="personal"><namePart type="given">Yimin</namePart><namePart type="family">Wei</namePart><affiliation>Pharmacokinetic Drug Analysis Laboratory and Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, North Dakota</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gloria A.</namePart><namePart type="family">Nygard</namePart><affiliation>Pharmacokinetic Drug Analysis Laboratory and Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, North Dakota</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Shari L.</namePart><namePart type="family">Ellertson</namePart><affiliation>Pharmacokinetic Drug Analysis Laboratory and Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, North Dakota</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Shoukry K.W.</namePart><namePart type="family">Khalil</namePart><affiliation>Pharmacokinetic Drug Analysis Laboratory and Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, North Dakota</affiliation><affiliation>Correspondence address: Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, ND 58105</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</genre><originInfo><publisher>Alan R. Liss, Inc.</publisher><place><placeTerm type="text">New York</placeTerm></place><dateIssued encoding="w3cdtf">1995</dateIssued><dateCaptured encoding="w3cdtf">1995-04-13</dateCaptured><dateValid encoding="w3cdtf">1995-07-17</dateValid><copyrightDate encoding="w3cdtf">1995</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><extent unit="figures">2</extent><extent unit="tables">4</extent><extent unit="references">24</extent></physicalDescription><abstract lang="en">Racemic hydroxychloroquine‐sulfate (HCQ‐sulfate) was administered to rats orally. Groups of 9 male and 9 female rats received doses of 0, 8, 16, or 24 mg/kg/day for 6 weeks, followed by a reduction of the higher doses to 8 mg/kg/day for the duration of the study. Whole blood samples were collected at 0, 3, 6, 8, and 10 weeks, and eleven tissues were harvested after the tenth week. The concentrations and enantiomer ratios of the parent drug and three metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ), were determined. The highest concentration of HCQ was found in the intestinal smooth muscle, and the lowest in the brain and adipose tissue. The highest concentrations of the metabolites were found in the liver, adrenals, and lung tissue. The metabolism of HCQ in the rats was found to be stereoselective with R/S > 1 for the drug and < 1 for the metabolites. Gender‐specific differences in the proportions of the drug and its metabolites and their enantiomers in blood and tissue were found. Varying dosages appeared to have only a temporary influence on blood concentrations and not to effect the enantiomer ratios in blood. Only a limited number of tissues exhibited significant differences between dose groups. 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