Metabolic activation of drugs by cytochrome P450 enzymes: Biochemical insights into mechanism-based inactivation by fibroblast growth factor receptor inhibitors and chemical approaches to attenuate reactive metabolite formation.

Metabolic activation of drugs by cytochrome P450 enzymes (P450) to chemically reactive electrophiles is commonly regarded as a key molecular-initiating event underpinning idiosyncratic drug-induced liver injury. However, apart from precipitating toxicities, these labile intermediates can be sequestered within the P450 active site and engender a unique form of irreversible inhibition known as mechanism-based inactivation (MBI) which bears profound clinical implications (i.e., drug-drug interactions, autoinhibition of hepatic elimination, time-dependent and/or nonlinear pharmacokinetics). Consequently, there has been considerable attempts to develop medicinal chemistry strategies to attenuate or abolish metabolic activation and its deleterious downstream effects (i.e., MBI). In this review, we will first summarize the fundamental aspects and consequences of P450 metabolic activation with a focus on MBI. Following which, we will share our recent discoveries on the arcane metabolic activation pathways of an emerging class of tyrosine kinase inhibitors known as the fibroblast growth factor receptor (FGFR) inhibitors which in turn unravelled mechanistic insights into the biochemical basis and pharmacokinetic implications of its MBI. Finally, we will discuss, using relevant examples from the literature as well as from our laboratory, limitations of existing chemical approaches to minimize metabolic activation and highlight a promising new paradigm which involves the rational deuteration of a drug molecule at its known bioactivation 'hot-spot' to shunt metabolism away from these aberrant pathways and reduce reactive metabolite formation.