Unusual Biotransformation Reactions of Drugs and Drug Candidates

Detailed assessment of the fate of drugs in nonclinical test species and humans is essential to ensure the safety and efficacy of medicines in patients. In this context, biotransformation of drugs and drug candidates has been an area of keen interest over many decades in the pharmaceutical industry as well as academia. Although many of the enzymes and biotransformation pathways involved in the metabolism of xenobiotics and more specifically drugs have been well characterized, each drug molecule is unique and constitutes specific challenges for the biotransformation scientist. In this mini-review written for the special issue on the occasion of the 50th Anniversary celebration of Drug Metabolism and Disposition and to celebrate contributions of F. Peter Guengerich, one of the pioneers of the drug metabolism field, recently reported "unusual" biotransformation reactions are presented. Scientific and technological advances in the "toolbox" of the biotransformation scientists are summarized. As the pharmaceutical industry continues to explore therapeutic modalities different from the traditional small molecule drugs, the new challenges confronting the biotransformation scientist as well as future opportunities are discussed. SIGNIFICANCE STATEMENT: For the biotransformation scientists, it is essential to share and be aware of unexpected biotransformation reactions so that they can increase their confidence in predicting metabolites of drugs in humans to ensure the safety and efficacy of these metabolites before the medicines reach large numbers of patients. The purpose of this review is to highlight recent observations of "unusual" metabolites so that the scientists working in the area of drug metabolism can strengthen their readiness in expecting the unexpected.