The effect of ageing on drug induced liver injury: insights from animal models

Abstract

Historically, older people (>65 years) were thought to be at increased risk of drug induced liver injury (DILI). This has not been well established empirically. This thesis aims to investigate the effect of ageing on DILI induced by paracetamol and isoniazid in male Fischer 344 rats. Young and old rats were treated via i.p. injection with toxic regimens of paracetamol, isoniazid or vehicle controls. After rats were euthanised, sera and liver were collected to measure drug and metabolite levels and assess for toxicity. Old age resulted in changes in paracetamol pharmacokinetics and decreased susceptibility to liver toxicity based on standard biomarkers. In contrast, hepatic DNA fragmentation significantly increased in old animals following a toxic insult compared to young. Different patterns of hepatotoxicity occurred with age following isoniazid insult. Young animals developed necrosis and increased circulating hepatotoxicity biomarkers, and old animals developed microvesicular steatosis. Apoptosis was not involved in the pathogenesis of hepatotoxicity but was altered with ageing. Our animal studies indicate that old age affects the pattern and risk of DILI from paracetamol or isoniazid differently. Future research is required to translate this in humans to guide therapeutic drug dosing and diagnosis of DILI in patients of all ages.