Embryotoxicity of artesunate in animal species related to drug tissue distribution and toxicokinetic profiles
Identifieur interne : 001A07 ( Main/Exploration ); précédent : 001A06; suivant : 001A08Embryotoxicity of artesunate in animal species related to drug tissue distribution and toxicokinetic profiles
Auteurs : Qigui Li [États-Unis] ; Yuanzheng Si [États-Unis] ; Kirsten S. Smith [États-Unis] ; Qiang Zeng [États-Unis] ; Peter J. Weina [États-Unis]Source :
- Birth Defects Research Part B: Developmental and Reproductive Toxicology [ 1542-9733 ] ; 2008-08.
Abstract
BACKGROUND: Injectable artesunate (AS) can cause fetal death and teratogenic effects in animals at levels below the human therapeutic dose. Similar toxicity has also been found for oral artemisinins in various animal species, but has not been found in humans. METHODS: Studies on tissue distribution (5 mg/kg) and toxicokinetics (TK, 30 mg/kg × 3) were conducted in pregnant (GD11–13) and non‐pregnant rats. RESULTS: TK profiles of AS showed that the two groups of rats were similar after a single AS dose but were significantly different after multiple doses. Following a daily dose for 3 days, no change in AS concentration was found in the pregnant animals, but a significant concentration decline was seen in the non‐pregnant rats on day 3. In addition, a higher conversion rate of AS to dihydroartemisinin (DHA) was detected in the pregnant rats after either single or multiple doses compared to non‐pregnant controls. The ratios of AUCDHA/AUCAS were 0.99–1.02 for the pregnant rats and 0.42–0.48 for non‐pregnant animals, resulting in a total AUCDHA D1–3 that was about 3.7‐fold higher in pregnant rats (15,049 ng·h/ml) than in non‐pregnant rats (4,015 ng·h/ml). Furthermore, the tissue/blood partition coefficients demonstrated that the level of radiolabeled AS that was distributed into uterus, placenta, and ovary was 2–4‐fold higher than in blood. CONCLUSIONS: TK data showed that unchanged AS and DHA in the blood of pregnant rats were 1.53‐ and 3.74‐fold, respectively, higher than those of non‐pregnant animals, which all likely relate to the severe embryotoxicity of AS, even with a low‐dosage regimen in pregnant animals. Birth Defects Res (Part B), 2008. Published 2008 Wiley‐Liss, Inc.
Url:
DOI: 10.1002/bdrb.20164
Affiliations:
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Weina</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:D5C06633CBF95FDEA9610584BAF3F75A4F70C454</idno><date when="2008" year="2008">2008</date><idno type="doi">10.1002/bdrb.20164</idno><idno type="url">https://api.istex.fr/ark:/67375/WNG-TX0XR3XM-2/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">001587</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001587</idno><idno type="wicri:Area/Istex/Curation">001587</idno><idno type="wicri:Area/Istex/Checkpoint">000912</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Checkpoint">000912</idno><idno type="wicri:doubleKey">1542-9733:2008:Li Q:embryotoxicity:of:artesunate</idno><idno type="wicri:Area/Main/Merge">001A15</idno><idno type="wicri:Area/Main/Curation">001A07</idno><idno type="wicri:Area/Main/Exploration">001A07</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main">Embryotoxicity of artesunate in animal species related to drug tissue distribution and toxicokinetic profiles</title><author><name sortKey="Li, Qigui" sort="Li, Qigui" uniqKey="Li Q" first="Qigui" last="Li">Qigui Li</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Department of Pharmacology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring</wicri:cityArea></affiliation><affiliation></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Correspondence address: Section Chief of Pharmacokinetics/Pharmacodynamics, Department of Pharmacology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring</wicri:cityArea></affiliation></author><author><name sortKey="Si, Yuanzheng" sort="Si, Yuanzheng" uniqKey="Si Y" first="Yuanzheng" last="Si">Yuanzheng Si</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Department of Pharmacology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring</wicri:cityArea></affiliation></author><author><name sortKey="Smith, Kirsten S" sort="Smith, Kirsten S" uniqKey="Smith K" first="Kirsten S." last="Smith">Kirsten S. Smith</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Department of Pharmacology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring</wicri:cityArea></affiliation></author><author><name sortKey="Zeng, Qiang" sort="Zeng, Qiang" uniqKey="Zeng Q" first="Qiang" last="Zeng">Qiang Zeng</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Department of Pharmacology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring</wicri:cityArea></affiliation></author><author><name sortKey="Weina, Peter J" sort="Weina, Peter J" uniqKey="Weina P" first="Peter J." last="Weina">Peter J. Weina</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Department of Pharmacology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring</wicri:cityArea></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Birth Defects Research Part B: Developmental and Reproductive Toxicology</title><title level="j" type="alt">BIRTH DEFECTS RESEARCH PART B: DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY</title><idno type="ISSN">1542-9733</idno><idno type="eISSN">1542-9741</idno><imprint><biblScope unit="vol">83</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="435">435</biblScope><biblScope unit="page" to="445">445</biblScope><biblScope unit="page-count">11</biblScope><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2008-08">2008-08</date></imprint><idno type="ISSN">1542-9733</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1542-9733</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">BACKGROUND: Injectable artesunate (AS) can cause fetal death and teratogenic effects in animals at levels below the human therapeutic dose. Similar toxicity has also been found for oral artemisinins in various animal species, but has not been found in humans. METHODS: Studies on tissue distribution (5 mg/kg) and toxicokinetics (TK, 30 mg/kg × 3) were conducted in pregnant (GD11–13) and non‐pregnant rats. RESULTS: TK profiles of AS showed that the two groups of rats were similar after a single AS dose but were significantly different after multiple doses. Following a daily dose for 3 days, no change in AS concentration was found in the pregnant animals, but a significant concentration decline was seen in the non‐pregnant rats on day 3. In addition, a higher conversion rate of AS to dihydroartemisinin (DHA) was detected in the pregnant rats after either single or multiple doses compared to non‐pregnant controls. The ratios of AUCDHA/AUCAS were 0.99–1.02 for the pregnant rats and 0.42–0.48 for non‐pregnant animals, resulting in a total AUCDHA D1–3 that was about 3.7‐fold higher in pregnant rats (15,049 ng·h/ml) than in non‐pregnant rats (4,015 ng·h/ml). Furthermore, the tissue/blood partition coefficients demonstrated that the level of radiolabeled AS that was distributed into uterus, placenta, and ovary was 2–4‐fold higher than in blood. CONCLUSIONS: TK data showed that unchanged AS and DHA in the blood of pregnant rats were 1.53‐ and 3.74‐fold, respectively, higher than those of non‐pregnant animals, which all likely relate to the severe embryotoxicity of AS, even with a low‐dosage regimen in pregnant animals. Birth Defects Res (Part B), 2008. Published 2008 Wiley‐Liss, Inc.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Maryland</li></region></list><tree><country name="États-Unis"><region name="Maryland"><name sortKey="Li, Qigui" sort="Li, Qigui" uniqKey="Li Q" first="Qigui" last="Li">Qigui Li</name></region><name sortKey="Li, Qigui" sort="Li, Qigui" uniqKey="Li Q" first="Qigui" last="Li">Qigui Li</name><name sortKey="Si, Yuanzheng" sort="Si, Yuanzheng" uniqKey="Si Y" first="Yuanzheng" last="Si">Yuanzheng Si</name><name sortKey="Smith, Kirsten S" sort="Smith, Kirsten S" uniqKey="Smith K" first="Kirsten S." last="Smith">Kirsten S. Smith</name><name sortKey="Weina, Peter J" sort="Weina, Peter J" uniqKey="Weina P" first="Peter J." last="Weina">Peter J. Weina</name><name sortKey="Zeng, Qiang" sort="Zeng, Qiang" uniqKey="Zeng Q" first="Qiang" last="Zeng">Qiang Zeng</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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