Biokinetics of chlorpromazine in primary rat and human hepatocytes and human HepaRG cells after repeated exposure

被引:18
作者
Broeders, Jessica J. W. [1 ]
Parmentier, Celine [2 ]
Truisi, Germaine L. [3 ,5 ]
Josse, Rozenn [4 ]
Alexandre, Eliane [2 ]
Savary, Camille C. [4 ]
Hewitt, Philip G. [3 ]
Mueller, Stefan O. [3 ,5 ]
Guillouzo, Andre [4 ]
Richert, Lysiane [2 ]
van Eijkeren, Jan C. H. [6 ]
Hermens, Joop L. M. [1 ]
Blaauboer, Bas J. [1 ]
机构
[1] Univ Utrecht, Inst Risk Assessment Sci, NL-3508 TD Utrecht, Netherlands
[2] Kaly Cell, Plobsheim, France
[3] Merck KGaA, Merck Serono, Nonclin Safety, Darmstadt, Germany
[4] Univ Rennes 1, Inst Natl Sante & Rech Med, U991, Rennes, France
[5] Karlsruhe Inst Technol, Inst Angew Biowissensch, D-76021 Karlsruhe, Germany
[6] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands
关键词
Biokinetics; Primary hepatocytes; HepaRG cells; Chlorpromazine; NOMINAL EFFECTIVE CONCENTRATIONS; COMPOUNDS IN-VITRO; ANTIPSYCHOTIC-DRUGS; LONG-TERM; LIVER; TOXICITY; EXPRESSION; TRANSPORTER; METABOLISM; ENZYMES;
D O I
10.1016/j.tiv.2014.08.012
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
Since drug induced liver injury is difficult to predict in animal models, more representative tests are needed to better evaluate these effects in humans. Existing in vitro systems hold great potential to detect hepatotoxicity of pharmaceuticals. In this study, the in vitro biokinetics of the model hepatotoxicant chlorpromazine (CPZ) were evaluated in three different liver cell systems after repeated exposure in order to incorporate repeated-dose testing into an in vitro assay. Primary rat and human hepatocytes, cultured in sandwich configuration and the human HepaRG cell line were treated daily with CPZ for 14 days. Samples were taken from medium, cells and well plastic at specific time points after the first and last exposure. The samples were analysed by HPLC-UV. to determine the amount of CPZ in these samples. Based on cytotoxicity assays, the three models were tested at 1-2 mu M CPZ, while the primary rat hepatocytes and the HepaRG cell line were in addition exposed to a higher concentration of 15-20 mu M. Overall, the mass balance of CPZ decreased in the course of 24 h, indicating the metabolism of the compound within the cells. The largest decrease in parent compound was seen in the primary cultures: in the HepaRG cell cultures the mass balance only decreased to 50%. CPZ accumulated in the cells during the 14-day repeated exposure. Possible explanations for the accumulation of CPZ are a decrease in Metabolism over time, inhibition of efflux transporters or binding to phospholipids. The biokinetics of CPZ differed between the three liver cell models and were influenced by specific cell properties as well as culture conditions. These results support the conclusion that in vitro biokinetics data are necessary to better interpret chemical-induced cytotoxicity data. (C) 2014 Elsevier Ltd. All rights reserved.
引用
收藏
页码:52 / 61
页数:10
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