Age-related changes in the hepatic pharmacology and toxicology of paracetamol

Abstract

Optimal pharmacotherapy is determined when the pharmacokinetics and pharmacodynamics of the drug are understood. However, the age-related changes in pharmacokinetics and pharmacodynamics, as well as the increased interindividual variation mean optimal dose selection are a challenge for prescribing in older adults. Poor understanding of how hepatic clearance and toxicity are different with age results in suboptimal dose selection, poor efficacy, and/or increased toxicity. Of particular concern is the analgesic paracetamol which has been in use for more than 50 years and is consumed by a large proportion of older adults. Paracetamol is considered to be a relatively safe drug; however, caution must be taken because of its potential for toxicity. Paracetamol-induced liver injury from accidental overdose accounts for up to 55% of cases in older adults. Better understanding of how age affects the hepatic clearance and toxicity of drugs will contribute to evidence-based prescribing for older people, leading to fewer adverse drug reactions without loss of benefit.

Figure 1

Hepatic pharmacology and toxicology in old age. (A) Pseudocapillarisation (thickening, defenestration, and basement membrane formation) of the liver sinusoidal endothelial cells (LSECs) may affect susceptibility to drug-induced liver injury (DILI); (B) Changes in protein binding in old age affect the amount of free drug available for clearance; (C) Dysregulation of Kupffer cell activation may alter inflammatory response to DILI; (D) Pseudocapillarisation of the LSECs, and any changes in transporters, may alter drug transfer from the blood to hepatocytes; (E) Age-related changes in hepatic metabolism affect drug clearance: phase I metabolism is reduced, and changes in phase II metabolism are less well understood; (F) Reduced glutathione (GSH) in old age increases injury by toxic metabolites; (G) Expression of hepatic transporters in response to drug toxicity is poorly described in old age and affects biliary excretion of drugs and their metabolites; (H) Changes in mitochondrial structure and function in old age alter response to reactive oxygen species and cell death pathways. Steps (E), (F), and (G) are regulated by nuclear factor E2-related factor 2 (Nrf-2) which has reduced hepatic expression in old age. Figure adapted from [24, 25].

Figure 2

Age-related pseudocapillarisation of the liver sinusoid impairs the transfer of lipids (chylomicrons remnants) and paracetamol across the fenestrated liver sinusoidal endothelial cells (LSECs). Adapted from Le Couteur et al., 2002 (20).

Figure 3

The effect of age on risk factors for paracetamol-induced hepatotoxicity and the potential mechanism through which they may act.

Figure 4

The effect of age on the hepatotoxic pathway for paracetamol-induced liver injury. At therapeutic doses, paracetamol metabolised primarily in the livervia the Phase II metabolism (conjugation). A small amount of drug undergoes Phase I CYP450- (CYP-)mediated N-hydroxylation to form N-acetyl-p-amino-benzoquinone immine (NAPQI), a toxic metabolite which is conjugated with hepatic glutathione (GSH) and is neutralised. The major metabolites are excreted via the urine or bile by Phase III transporters. Saturation of conjugation pathways results in increased use of the CYP450 pathway, increased NAPQI formation, and increased depletion of hepatic glutathione. NAPQI can cause injury through direct cell stress, direct mitochondrial inhibition, or through immune reactions. Initial injury leads to mitochondrial dysfunction leading to either apoptosis of damaged cells, or necrosis with recovery, chronic liver injury or actual liver failure, and death as potential outcomes. Additionally, necrosis can stimulate the inflammatory response leading to cytokine release and further potentiation of the immune reaction. Ageing can act at multiple parts of the pathway to either increase (↑) or decrease (↓) susceptibility to hepatotoxicity. It must be noted, however, that this is likely to vary between individuals. The effect of ageing on Phase III transporters is somewhat unknown (?) in humans. Picture adapted from Russmann et.al., 2009 [141].