Managing the challenge of chemically reactive metabolites in drug development

Abstract

The normal metabolism of drugs can generate metabolites that have intrinsic chemical reactivity towards cellular molecules, and therefore have the potential to alter biological function and initiate serious adverse drug reactions. Here, we present an assessment of the current approaches used for the evaluation of chemically reactive metabolites. We also describe how these approaches are being used within the pharmaceutical industry to assess and minimize the potential of drug candidates to cause toxicity. At early stages of drug discovery, iteration between medicinal chemistry and drug metabolism can eliminate perceived reactive metabolite-mediated chemical liabilities without compromising pharmacological activity or the need for extensive safety evaluation beyond standard practices. In the future, reactive metabolite evaluation may also be useful during clinical development for improving clinical risk assessment and risk management. Currently, there remains a huge gap in our understanding of the basic mechanisms that underlie chemical stress-mediated adverse reactions in humans. This review summarizes our views on this complex topic, and includes insights into practices considered by the pharmaceutical industry.

Liver X receptor α (LXRα/NR1H3) regulates differentiation of hepatocyte-like cells via reciprocal regulation of HNF4α

“…HepaRG cells have been used in a variety of studies, including those involving liver toxicity [49,50], hepatitis viruses infection [51], human hepatic diseases and differentiation. The currently used differentiation procedure takes 4 weeks in DMSO-treated medium.…”

Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury

“…Skin is the tissue most commonly targeted by immune cells; however, other organs, including the liver, can be damaged either in isolation or as part of a generalized hypersensitivity syndrome. 1 T-lymphocytes are believed to cause drug-induced skin injury through the action of cytokines and cytolytic molecules. To stimulate a T-cell response the drug must bind to human leukocyte antigen (HLA) and in some way crosslink specific T-cell receptors.…”

Systems biology tools for toxicology

“…When the dose of reactive metabolites exceeds the capacity of this defence system to replenish glutathione through new synthesis, glutathione depletion occurs. For a variety of toxic compounds, it has been found that the depletion of glutathione precedes the covalent binding of chemically reactive metabolites to cellular macromolecules, oxidative stress and, ultimately, organelle injury with the potential for liver failure and death (Park et al 2011). A more complete understanding of the events that lead to hepatic glutathione depletion might therefore highlight new and sensitive biomarkers and provide insights into key steps in glutathione production, thereby leading to improvements in risk assessment for new, and existing, drugs and xenobiotics.…”