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Investigations into the liver effects of ximelagatran using high content screening of primary human hepatocyte cultures.

Abstract：

BACKGROUND:Ximelagatran, the first oral agent in the new class of direct thrombin inhibitors, was withdrawn from the market due to increased rates of liver enzyme elevations in long-term treatments. Despite intensive pre clinical investigations the cellular mechanisms behind the observed hepatic effects remain unknown. OBJECTIVE:The aim of this study was to assess drug-induced cytotoxicity in primary human hepatocyte cultures by ximelagatran and other reference pharmaceutical agents with known in vivo hepatotoxic profiles. METHODS:Drugs cause liver injury by many distinct mechanisms that result in abnormal cellular functioning and different patterns of injury. To address many potential toxic mechanisms in a human-relevant model, freshly isolated human hepatocytes were used in automated imaging assays. Ximelagatran was used as a test compound to study biochemical and morphological changes in human hepatocytes. In addition, 11 control, reference and comparator compounds with known liver-toxic potential in humans were used. The response to these compounds was assessed across five different hepatocyte donor preparations. RESULTS:Cytotoxicity induced by a number of compounds was quantitatively monitored using an automated imaging technique. A variety of morphological changes in hepatocyte cytoskeleton and mitochondrial function could be identified at sublethal doses of test compounds. Doses of ximelagatran up to 500 microM did not cause a cytotoxic response in the majority of preparations and no subcytotoxic response was observed at doses below 125 microM. CONCLUSIONS:The experiments described here demonstrate that primary human hepatocytes may be used in a medium-throughput format for screening using imaging-based assays for the identification of cellular responses. Overall, it is concluded that ximelagatran did not cause a significant decrease in cell viability when incubated for 24 h at considerably higher concentrations than are found in plasma following therapeutic dosing.

journal_name

Expert Opin Drug Saf

journal_title

Expert opinion on drug safety

authors

Ainscow EK,Pilling JE,Brown NM,Orme AT,Sullivan M,Hargreaves AC,Cooke EL,Sullivan E,Carlsson S,Andersson TB

doi

10.1517/14740338.7.4.351

subject

Has Abstract

pub_date

2008-07-01 00:00:00

pages

351-65

issue

eissn

1474-0338

issn

1744-764X

journal_volume

pub_type

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Investigations into the liver effects of ximelagatran using high content screening of primary human hepatocyte cultures.