Pharmacokinetic and toxicodynamic concepts in idiosyncratic, drug-induced liver injury

Idiosyncratic drug-induced liver injury (IDILI) causes morbidity and mortality in patients and leads to curtailed use of efficacious pharmaceuticals. Unlike intrinsically toxic reactions, which depend on dose, IDILI occurs in a minority of patients at therapeutic doses. Much remains unknown about causal links among drug exposure, a mode of action, and liver injury. Consequently, numerous hypotheses about IDILI pathogenesis have arisen.

Pharmacokinetic and toxicodynamic characteristics underlying current hypotheses of IDILI etiology are discussed and illustrated graphically.

Hypotheses to explain IDILI etiology all involve alterations in pharmacokinetics, which lead to plasma drug concentrations that rise above a threshold for toxicity, or in toxicodynamics, which result in a lowering of the toxicity threshold. Altered pharmacokinetics arise, for example, from changes in drug metabolism or from transporter polymorphisms. A lowered toxicity threshold can arise from drug-induced mitochondrial injury, accumulation of toxic endogenous factors or harmful immune responses. Newly developed, interactive freeware (DemoTox-PK; https://bit.ly/DemoTox-PK) allows the user to visualize how such alterations might lead to a toxic reaction. The illustrations presented provide a framework for conceptualizing idiosyncratic reactions and could serve as a stimulus for future discussion, education, and research into modes of action of IDILI.