RT Journal Article
SR Electronic
T1 Cytotoxicity evaluation of chloroquine and hydroxychloroquine in multiple cell lines and tissues by dynamic imaging system and PBPK model
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.22.056762
DO 10.1101/2020.04.22.056762
A1 Jianling Yang
A1 Meng Wu
A1 Xu Liu
A1 Qi Liu
A1 Zhengyang Guo
A1 Xueting Yao
A1 Yang Liu
A1 Cheng Cui
A1 Haiyan Li
A1 Chunli Song
A1 Dongyang Liu
A1 Lixiang Xue
YR 2020
UL http://biorxiv.org/content/early/2020/04/27/2020.04.22.056762.abstract
AB Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used in treating COVID-19 patients recently. However, both drugs have some contradictions and rare but severe side effects, such as hypoglycemia, retina and cardiac toxicity. To further uncover the toxicity profile of CQ and HCQ in different tissues, we evaluated the cytotoxicity of them in 8 cell lines, and further adopted the physiologically-based pharmacokinetic models (PBPK) 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 hours by IncuCyte S3, which could perform long-term continuous image and video of cells upon CQ or HCQ treatment. CC50 and the ratio of tissue trough concentrations to CC50 (RTTCC) were brought into predicted toxicity profiles. The CC50 at 24 h, 48 h, 72 h of CQ and HCQ decreased in the time-dependent manner, which indicates the accumulative cytotoxic effect. HCQ was found to be less toxic in 7 cell types except cardiomyocytes H9C2 cells (CC50-48 h=29.55 μM; CC50-72 h=15.26 μM). In addition, RTTCC is significant higher in CQ treatment group compared to HCQ group, which indicates that relative safety of HCQ. Both CQ and HCQ have certain cytotoxicity in time dependent manner which indicates the necessity of short period administration clinically. HCQ has the less impact in 7 cell lines proliferation and less toxicity compared to CQ in heart, liver, kidney and lung.SARS-CoV-2Severe Acute Respiratory Syndrome Coronavirus 2ARDSAcute respiratory distress syndromeCQChloroquineHCQHydroxychloroquineCOVID-19Coronavirus disease 2019SLESystemic lupus erythematosusEC50Concentration for 50% of maximal effectCC50The median cytotoxic concentrationPBPKPhysiologically-based pharmacokinetic modelsRTTCCRatio of tissue trough concentration vs CC50)