Cytotoxicity Evaluation of Chloroquine and Hydroxychloroquine in Multiple Cell Lines and Tissues by Dynamic Imaging System and Physiologically Based Pharmacokinetic Model.
Identifieur interne : 000282 ( Main/Corpus ); précédent : 000281; suivant : 000283Cytotoxicity Evaluation of Chloroquine and Hydroxychloroquine in Multiple Cell Lines and Tissues by Dynamic Imaging System and Physiologically Based Pharmacokinetic Model.
Auteurs : Jianling Yang ; Zhengyang Guo ; Xu Liu ; Qi Liu ; Meng Wu ; Xueting Yao ; Yang Liu ; Cheng Cui ; Haiyan Li ; Chunli Song ; Dongyang Liu ; Lixiang XueSource :
- Frontiers in pharmacology [ 1663-9812 ] ; 2020.
Abstract
Chloroquine (CQ) and hydroxychloroquine (HCQ) have been challenged in treating COVID-19 patients and still under debate due to the uncertainty regarding the effectiveness and safety, and there is still lack of the systematic study on the toxicity of these two drugs. To further uncover the toxicity profile of CQ and HCQ in different tissues, we evaluated the cytotoxicity of them in eight cell lines and further adopted the physiologically based pharmacokinetic models to predict the tissue risk, respectively. Retina, myocardium, lung, liver, kidney, vascular endothelium, and intestinal epithelium originated cells were included in the toxicity evaluation of CQ and HCQ, respectively. The proliferation pattern was monitored in 0-72 h by IncuCyte S3. CC50 and the ratio of tissue trough concentrations to CC50 (RTTCC) were brought into predicted toxicity profiles. Compared to CQ, HCQ was found to be less toxic in six cell types except Hep3B and Vero cells. In addition, RTTCC was significantly higher in CQ treatment group compared to HCQ group, which indicates relative safety of HCQ. To further simulate the situation of the COVID-19 patients who suffered the dyspnea and hypoxemia, we also tested the cytotoxicity upon hypoxia and normoxia (1, 5 vs. 21% O2). It was found that the cytotoxicity of CQ was more sensitive to hypoxia compared with that of HCQ, particularly in liver originated cells. Both CQ and HCQ showed cytotoxicity in time-dependent manner which indicates the necessity of short period administration clinically.
DOI: 10.3389/fphar.2020.574720
PubMed: 33658924
PubMed Central: PMC7919379
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Third Hospital, Beijing, China.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Qi" sort="Liu, Qi" uniqKey="Liu Q" first="Qi" last="Liu">Qi Liu</name><affiliation><nlm:affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Wu, Meng" sort="Wu, Meng" uniqKey="Wu M" first="Meng" last="Wu">Meng Wu</name><affiliation><nlm:affiliation>Center of Basic Medicine Research (CBMR), Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Yao, Xueting" sort="Yao, Xueting" uniqKey="Yao X" first="Xueting" last="Yao">Xueting Yao</name><affiliation><nlm:affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Yang" sort="Liu, Yang" uniqKey="Liu Y" first="Yang" last="Liu">Yang Liu</name><affiliation><nlm:affiliation>Center of Basic Medicine Research (CBMR), Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Cui, Cheng" sort="Cui, Cheng" uniqKey="Cui C" first="Cheng" last="Cui">Cheng Cui</name><affiliation><nlm:affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Li, Haiyan" sort="Li, Haiyan" uniqKey="Li H" first="Haiyan" last="Li">Haiyan Li</name><affiliation><nlm:affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Song, Chunli" sort="Song, Chunli" uniqKey="Song C" first="Chunli" last="Song">Chunli Song</name><affiliation><nlm:affiliation>Department of Orthopedics, Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Dongyang" sort="Liu, Dongyang" uniqKey="Liu D" first="Dongyang" last="Liu">Dongyang Liu</name><affiliation><nlm:affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Xue, Lixiang" sort="Xue, Lixiang" uniqKey="Xue L" first="Lixiang" last="Xue">Lixiang Xue</name><affiliation><nlm:affiliation>Center of Basic Medicine Research (CBMR), Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:33658924</idno><idno type="pmid">33658924</idno><idno type="doi">10.3389/fphar.2020.574720</idno><idno type="pmc">PMC7919379</idno><idno type="wicri:Area/Main/Corpus">000282</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000282</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Cytotoxicity Evaluation of Chloroquine and Hydroxychloroquine in Multiple Cell Lines and Tissues by Dynamic Imaging System and Physiologically Based Pharmacokinetic Model.</title><author><name sortKey="Yang, Jianling" sort="Yang, Jianling" uniqKey="Yang J" first="Jianling" last="Yang">Jianling Yang</name><affiliation><nlm:affiliation>Center of Basic Medicine Research (CBMR), Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Guo, Zhengyang" sort="Guo, Zhengyang" uniqKey="Guo Z" first="Zhengyang" last="Guo">Zhengyang Guo</name><affiliation><nlm:affiliation>Center of Basic Medicine Research (CBMR), Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Xu" sort="Liu, Xu" uniqKey="Liu X" first="Xu" last="Liu">Xu Liu</name><affiliation><nlm:affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation><affiliation><nlm:affiliation>Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Qi" sort="Liu, Qi" uniqKey="Liu Q" first="Qi" last="Liu">Qi Liu</name><affiliation><nlm:affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Wu, Meng" sort="Wu, Meng" uniqKey="Wu M" first="Meng" last="Wu">Meng Wu</name><affiliation><nlm:affiliation>Center of Basic Medicine Research (CBMR), Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Yao, Xueting" sort="Yao, Xueting" uniqKey="Yao X" first="Xueting" last="Yao">Xueting Yao</name><affiliation><nlm:affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Yang" sort="Liu, Yang" uniqKey="Liu Y" first="Yang" last="Liu">Yang Liu</name><affiliation><nlm:affiliation>Center of Basic Medicine Research (CBMR), Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Cui, Cheng" sort="Cui, Cheng" uniqKey="Cui C" first="Cheng" last="Cui">Cheng Cui</name><affiliation><nlm:affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Li, Haiyan" sort="Li, Haiyan" uniqKey="Li H" first="Haiyan" last="Li">Haiyan Li</name><affiliation><nlm:affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Song, Chunli" sort="Song, Chunli" uniqKey="Song C" first="Chunli" last="Song">Chunli Song</name><affiliation><nlm:affiliation>Department of Orthopedics, Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Dongyang" sort="Liu, Dongyang" uniqKey="Liu D" first="Dongyang" last="Liu">Dongyang Liu</name><affiliation><nlm:affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Xue, Lixiang" sort="Xue, Lixiang" uniqKey="Xue L" first="Lixiang" last="Xue">Lixiang Xue</name><affiliation><nlm:affiliation>Center of Basic Medicine Research (CBMR), Peking University Third Hospital, Beijing, China.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Frontiers in pharmacology</title><idno type="ISSN">1663-9812</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Chloroquine (CQ) and hydroxychloroquine (HCQ) have been challenged in treating COVID-19 patients and still under debate due to the uncertainty regarding the effectiveness and safety, and there is still lack of the systematic study on the toxicity of these two drugs. To further uncover the toxicity profile of CQ and HCQ in different tissues, we evaluated the cytotoxicity of them in eight cell lines and further adopted the physiologically based pharmacokinetic models to predict the tissue risk, respectively. Retina, myocardium, lung, liver, kidney, vascular endothelium, and intestinal epithelium originated cells were included in the toxicity evaluation of CQ and HCQ, respectively. The proliferation pattern was monitored in 0-72 h by IncuCyte S3. CC50 and the ratio of tissue trough concentrations to CC50 (R<sub>TTCC</sub>) were brought into predicted toxicity profiles. Compared to CQ, HCQ was found to be less toxic in six cell types except Hep3B and Vero cells. In addition, R<sub>TTCC</sub> was significantly higher in CQ treatment group compared to HCQ group, which indicates relative safety of HCQ. To further simulate the situation of the COVID-19 patients who suffered the dyspnea and hypoxemia, we also tested the cytotoxicity upon hypoxia and normoxia (1, 5 vs. 21% O<sub>2</sub>). It was found that the cytotoxicity of CQ was more sensitive to hypoxia compared with that of HCQ, particularly in liver originated cells. Both CQ and HCQ showed cytotoxicity in time-dependent manner which indicates the necessity of short period administration clinically.</div></front></TEI><pubmed><MedlineCitation Status="PubMed-not-MEDLINE" Owner="NLM"><PMID Version="1">33658924</PMID><DateRevised><Year>2021</Year><Month>03</Month><Day>05</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Print">1663-9812</ISSN><JournalIssue CitedMedium="Print"><Volume>11</Volume><PubDate><Year>2020</Year></PubDate></JournalIssue><Title>Frontiers in pharmacology</Title><ISOAbbreviation>Front Pharmacol</ISOAbbreviation></Journal><ArticleTitle>Cytotoxicity Evaluation of Chloroquine and Hydroxychloroquine in Multiple Cell Lines and Tissues by Dynamic Imaging System and Physiologically Based Pharmacokinetic Model.</ArticleTitle><Pagination><MedlinePgn>574720</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.3389/fphar.2020.574720</ELocationID><Abstract><AbstractText>Chloroquine (CQ) and hydroxychloroquine (HCQ) have been challenged in treating COVID-19 patients and still under debate due to the uncertainty regarding the effectiveness and safety, and there is still lack of the systematic study on the toxicity of these two drugs. To further uncover the toxicity profile of CQ and HCQ in different tissues, we evaluated the cytotoxicity of them in eight cell lines and further adopted the physiologically based pharmacokinetic models to predict the tissue risk, respectively. Retina, myocardium, lung, liver, kidney, vascular endothelium, and intestinal epithelium originated cells were included in the toxicity evaluation of CQ and HCQ, respectively. The proliferation pattern was monitored in 0-72 h by IncuCyte S3. CC50 and the ratio of tissue trough concentrations to CC50 (R<sub>TTCC</sub>) were brought into predicted toxicity profiles. Compared to CQ, HCQ was found to be less toxic in six cell types except Hep3B and Vero cells. In addition, R<sub>TTCC</sub> was significantly higher in CQ treatment group compared to HCQ group, which indicates relative safety of HCQ. To further simulate the situation of the COVID-19 patients who suffered the dyspnea and hypoxemia, we also tested the cytotoxicity upon hypoxia and normoxia (1, 5 vs. 21% O<sub>2</sub>). It was found that the cytotoxicity of CQ was more sensitive to hypoxia compared with that of HCQ, particularly in liver originated cells. Both CQ and HCQ showed cytotoxicity in time-dependent manner which indicates the necessity of short period administration clinically.</AbstractText><CopyrightInformation>Copyright © 2020 Yang, Guo, Liu, Liu, Wu, Yao, Liu, Cui, Li, Song, Liu and Xue.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Yang</LastName><ForeName>Jianling</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Center of Basic Medicine Research (CBMR), Peking University Third Hospital, Beijing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Guo</LastName><ForeName>Zhengyang</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>Center of Basic Medicine Research (CBMR), Peking University Third Hospital, Beijing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Xu</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Qi</ForeName><Initials>Q</Initials><AffiliationInfo><Affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wu</LastName><ForeName>Meng</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Center of Basic Medicine Research (CBMR), Peking University Third Hospital, Beijing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yao</LastName><ForeName>Xueting</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Yang</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Center of Basic Medicine Research (CBMR), Peking University Third Hospital, Beijing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cui</LastName><ForeName>Cheng</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Haiyan</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Song</LastName><ForeName>Chunli</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Orthopedics, Peking University Third Hospital, Beijing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Dongyang</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Xue</LastName><ForeName>Lixiang</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Center of Basic Medicine Research (CBMR), Peking University Third Hospital, Beijing, China.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>11</Month><Day>20</Day></ArticleDate></Article><MedlineJournalInfo><Country>Switzerland</Country><MedlineTA>Front Pharmacol</MedlineTA><NlmUniqueID>101548923</NlmUniqueID><ISSNLinking>1663-9812</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">chloroquine and hydroxychloroquine</Keyword><Keyword MajorTopicYN="N">cytotoxicity</Keyword><Keyword MajorTopicYN="N">dynamic imaging system</Keyword><Keyword MajorTopicYN="N">physiologically based pharmacokinetic model</Keyword><Keyword MajorTopicYN="N">ratio of tissue trough concentrations</Keyword></KeywordList><CoiStatement>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2020</Year><Month>06</Month><Day>23</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>10</Month><Day>12</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2021</Year><Month>3</Month><Day>4</Day><Hour>5</Hour><Minute>53</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2021</Year><Month>3</Month><Day>5</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2021</Year><Month>3</Month><Day>5</Day><Hour>6</Hour><Minute>1</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">33658924</ArticleId><ArticleId IdType="doi">10.3389/fphar.2020.574720</ArticleId><ArticleId IdType="pii">574720</ArticleId><ArticleId IdType="pmc">PMC7919379</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>BMJ. 2020 May 14;369:m1849</Citation><ArticleIdList><ArticleId IdType="pubmed">32409561</ArticleId></ArticleIdList></Reference><Reference><Citation>Lupus. 2017 Oct;26(12):1304-1308</Citation><ArticleIdList><ArticleId IdType="pubmed">28355984</ArticleId></ArticleIdList></Reference><Reference><Citation>Cell Res. 2020 Mar;30(3):269-271</Citation><ArticleIdList><ArticleId 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