Yondelis (ET-743) is a promising
antitumor drug with hepatotoxic properties in animals and humans. Here the hypothesis was tested that
dexamethasone can ameliorate manifestations of
yondelis-induced hepatotoxicity in the female Wistar rat, which is the animal species with the highest sensitivity toward the adverse hepatic effect of
yondelis. Hepatotoxicity was adjudged by measurement of plasma levels of
alkaline phosphatase,
aspartate aminotransferase, and
bilirubin, and by liver histopathology.
Yondelis (40 micro g/kg i.v.) alone caused a dramatic elevation of plasma
alkaline phosphatase,
aspartate aminotransferase, and
bilirubin levels, and degeneration and patchy focal
necrosis of bile duct epithelial cells. Pretreatment of rats with
dexamethasone (5-20 mg/kg, p.o.) 24 h before
yondelis ameliorated or abrogated the biochemical and histopathological manifestations of
yondelis-induced liver changes. In contrast, when
dexamethasone was administered simultaneously with
yondelis, its toxicity was not reduced. Pretreatment with
dexamethasone (10 mg/kg) also reversed the gene expression changes induced by
yondelis in rat liver. However,
dexamethasone pretreatment did not interfere with the antitumor efficacy of
yondelis in rats bearing the 13762 mammary
carcinoma or in four murine models.
Dexamethasone (10 mg/kg) administered 24 h before
yondelis decreased hepatic levels of
yondelis dramatically compared with those obtained after administration of
yondelis alone, whereas
yondelis plasma levels after the
drug combination were not markedly different from those in rats on
yondelis alone. The results suggest that pretreatment with high-dose
dexamethasone effectively protects rats against
yondelis-mediated hepatic damage by decreasing hepatic exposure to
yondelis, perhaps linked to induction of metabolism by
cytochrome P450 enzymes. Pretreatment with high-dose
dexamethasone should be investigated in patients who receive
yondelis to ameliorate its unwanted effect on the liver.