Mechanism-based inactivation of CYP450 enzymes: a case study of lapatinib

Abstract

Mechanism-based inactivation (MBI) of CYP450 enzymes is a unique form of inhibition in which the enzymatic machinery of the victim is responsible for generation of the reactive metabolite. This precondition sets up a time-dependency for the inactivation process, a hallmark feature that characterizes all MBI. Yet, MBI itself is a complex biochemical phenomenon that operates in different modes, namely, covalent binding to apoprotein, covalent binding of the porphyrin group and also complexation of the catalytic iron. Using lapatinib as a recent example of toxicological interest, we present an example of a mixed-function MBI that can confound clinical drug–drug interactions manifestation. Lapatinib exhibits both covalent binding to the apoprotein and formation of a metabolite-intermediate complex in an enzyme-selective manner (CYP3A4 versus CYP3A5), each with different reactive metabolites. The clinical implication of this effect is also contingent upon genetic polymorphisms of the enzyme involved as well as the co-administration of other substrates, inhibitors or inducers, culminating in drug–drug interactions. This understanding recapitulates the importance of applying isoform-specific mechanistic investigations to develop customized strategies to manage such outcomes.

• CYP3A
• drug–drug interaction
• lapatinib
• mechanism-based inactivation
• toxicity

Acknowledgements

This project is funded by the Singapore Ministry of Education's (MOE) Academic Research Grants R -148-000-187-112 (HKH) and R-148-000-135-112 (ECYC) and National Institutes of Health (NIH) National Institute of General Medical Sciences (NIGMS) Grant GM32165 (KDH) and the UNCF-Merck Science Initiative (KDH). CYC is supported by the NUS President Graduate Fellowship.

This review is written in memory of Professor Sidney D. Nelson, who has inspired each of the co-authors both intellectually and personally with his transformative thinking and compelling reasoning.

Declaration of interest

This project is funded by the Singapore Ministry of Education’s (MOE) Academic Research Grants R -148-000-187-112 (H. K. H.) and R-148-000-135-112 (E. C. Y. C.) and National Institutes of Health (NIH) National Institute of General Medical Sciences (NIGMS) Grant GM32165 (K. D. H.) and the UNCF-Merck Science Initiative (K D. H.). C. Y. C. is supported by the NUS President Graduate Fellowship.