INTRODUCTION

A number of withdrawn drugs are known to undergo bioactivation by a range of drug metabolizing enzymes to chemically reactive metabolites that bind covalently to protein and DNA resulting in organ toxicity and carcinogenesis, respectively. An important goal in drug discovery is to identify structural sites of bioactivation within discovery molecules for providing strategic modifications that eliminate or minimize reactive metabolite formation, while maintaining target potency, selectivity and desired pharmacokinetic properties leading to the development of efficacious and nontoxic drugs.

AREAS COVERED

This review covers experimental techniques currently used to detect reactive drug metabolites and provides recent examples where information from mechanistic in vitro studies was successfully used to redesign candidate drugs leading to blocked or minimized bioactivation. Reviewed techniques include in vitro radiolabeled drug covalent binding to protein and reactive metabolite trapping with reagents such as glutathione, cyanide, semicarbazide and DNA bases. Case studies regarding reactive metabolite detection using a combination of varied techniques, including liquid chromatography-tandem mass spectrometry and NMR analyses and subsequent structural modification are discussed.

EXPERT OPINION

Information derived from state-of-art mechanistic drug metabolism studies can be used successfully to direct medicinal chemistry towards the synthesis of candidate drugs devoid of bioactivation liabilities, while maintaining desired pharmacology and pharmacokinetic properties.