METABOLIC ACTIVATION OF FIBROBLAST GROWTH FACTOR RECEPTOR INHIBITORS BY CYTOCHROME P450: MECHANISTIC INVESTIGATIONS INTO THE BIOCHEMICAL BASIS AND PHARMACOKINETIC IMPLICATIONS OF MECHANISM-BASED INACTIVATION

Abstract

Metabolic activation of drugs by drug-metabolizing cytochrome P450 (P450) enzymes to chemically reactive metabolites 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, time-dependent inhibition known as mechanism-based inactivation (MBI) which bears profound clinical implications (i.e., drug-drug interactions). Consequently, there has been considerable endeavors by pharmaceutical companies to attenuate or abolish metabolic activation at these bioactivation ‘hot-spots’ in new chemical entities to mitigate its deleterious downstream effects. However, this is often an iterative process whose success critically hinges on a firm understanding of its underpinning metabolic activation. In this thesis, we deciphered the arcane metabolic activation pathways of an emerging class of tyrosine kinase inhibitors known as the fibroblast growth factor receptor (FGFR) inhibitors for the first time. These findings contribute novel and crucial knowledge on the biochemical basis and pharmacokinetic implications of P450-mediated metabolic activation of FGFR inhibitors and will help advance the drug development, regulatory and utilization continuum of this nascent class of tyrosine kinase inhibitors.