Ximelagatran increases membrane fluidity and changes membrane lipid composition in primary human hepatocytes.

ABSTRACT

Ximelagatran, the first oral agent in the new class of direct thrombin inhibitors, was withdrawn from the market due to a potential risk of severe liver injury. Increased rates of liver enzyme elevations had been observed during clinical trials of chronic use. Despite intensive preclinical investigations the cellular mechanisms behind the observed hepatic effects remain unknown. The aim of this study was to investigate whether ximelagatran has an effect on the plasma membrane fluidity and the membrane lipid composition which may be important for the cell integrity. After 1h exposure of primary human hepatocytes with 10 or 100 microM ximelagatran, a significant elevation of membrane fluidity was observed. This elevation was maintained at 24h, but diminished at 48 h exposure. As changed membrane lipid composition could influence membrane fluidities, changes in membrane lipid profiles were also studied. After 1h exposure, the phosphatidylcholine/phosphatidylethanolamine molar ratio decreased, whereas the total cholesterol/phospholipid molar ratio decreased after a 48 h exposure. The change in membrane fluidity and lipid composition in human hepatocytes exposed to ximelagatran might indicate changes in plasma membrane properties that in susceptible subjects, could result in loss of membrane integrity and leakage of cellular proteins.