The Importance of Patient-Specific Factors for Hepatic Drug Response and Toxicity

Abstract

Responses to drugs and pharmacological treatments differ considerably between individuals. Importantly, only 50%-75% of patients have been shown to react adequately to pharmacological interventions, whereas the others experience either a lack of efficacy or suffer from adverse events. The liver is of central importance in the metabolism of most drugs. Because of this exposed status, hepatotoxicity is amongst the most common adverse drug reactions and hepatic liabilities are the most prevalent reason for the termination of development programs of novel drug candidates. In recent years, more and more factors were unveiled that shape hepatic drug responses and thus underlie the observed inter-individual variability. In this review, we provide a comprehensive overview of different principle mechanisms of drug hepatotoxicity and illustrate how patient-specific factors, such as genetic, physiological and environmental factors, can shape drug responses. Furthermore, we highlight other parameters, such as concomitantly prescribed medications or liver diseases and how they modulate drug toxicity, pharmacokinetics and dynamics. Finally, we discuss recent progress in the field of in vitro toxicity models and evaluate their utility in reflecting patient-specific factors to study inter-individual differences in drug response and toxicity, as this understanding is necessary to pave the way for a patient-adjusted medicine.

Keywords: drug-induced liver injury; hepatotoxicity; liver disease; pharmacogenetics.

Figure 1

Drugs for which pharmacogenetic testing is recommended or required by major regulatory authorities: (a) Medications that require pharmacogenetic testing are indicated with “X”. If testing is only recommended, drugs are indicated with “●”. Requirements and recommendations by American (FDA), European (EMA) and Japanese (PMDA) regulatory authorities are shown. Note that only few medications (indicated in bold red) overlap with drugs for which prescribing action is recommended by the Clinical Pharmacogenetics Implementation Consortium (compare Table 1); (b) Venn diagram visualizing the overlap of drugs for which pharmacogenetic testing is required or recommended across FDA, EMA and PMDA.

Figure 2

Schematic depiction of hepatotoxic drugs and their respective mitochondrial targets. Medications can exert toxic effects on mitochondria by targeting a variety of different processes, such as inhibition of mitochondrial respiratory chain components, uncoupling of oxidative phosphorylation or inhibition of β-oxidation and/or depletion of carnitine or coenzyme A. Some compounds, mostly antiretrovirals, can furthermore cause mitochondrial DNA depletion. Mitochondrial damage can result in opening of the mitochondrial permeability transition pore, causing loss of membrane potential, mitochondrial swelling and cell death by apoptosis or necrosis. The associated references are shown in Table 3.

Figure 3

Proposed mechanisms of metabolic activation of ximelagatran. mARC2 in the outer mitochondrial membrane reduces ximelagatran to a reactive metabolite, which in turn inhibits mitochondrial respiration and causes hepatotoxicity.