Covalent Drug–Protein Adducts: An Exploration of Their Role in Drug‐Induced Liver and General Organ Toxicity

Abstract

Overcoming drug induced liver injury continues to represent a challenge for the pharmaceutical industry. Reducing metabolic drug bioactivation is a medicinal chemistry strategy that continues to represent the main platform to minimize this liability. Leveraging covalent binding studies to predict potential for liver toxicity has been widely investigated and appears to have some merit when performed in hepatocyte preparations and integrated with, for example, daily dose but clearly has limitations even when supplemented with data from additional assays that assess hepatotoxicity risk. Here we move beyond a discussion of acute liver toxicity as addressed by chemical synthetic strategies (focus on drug design) by exploring the underlying biochemical science and challenges that still exist regarding the predisposition of some people to idiosyncratic liver toxicity (focus on the individual). The hope is that the positive trajectory of the developing science in this area has the potential to deliver safer drugs to patients in need.