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



Introduction:

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.


Areas covered:

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


Expert opinion:

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.


Keywords:

Drug toxicity; idiosyncrasy; idiosyncratic; liver injury; liver toxicity; pharmacodynamics; pharmacokinetics; toxicity threshold; toxicodynamics.



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