Age-Related Changes in the Hepatic Pharmacology and Toxicology of Paracetamol

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].