Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug-drug interactions and hepatotoxicity.

摘要: Tyrosine kinase inhibitors (TKI) are small heterocyclic molecules targeting transmembrane and cytoplasmic tyrosine kinases that have met with considerable success in clinical oncology. TKI associated toxicities including liver injury may be serious even life-threatening. Many of them require warnings drug labeling against injury, five Black Box Warning (BBW) labels. Although drug-induced is a matter industrial concern, little known about the underlying mechanisms likely involve reactive metabolites (RM). RM electrophiles or radicals originating from metabolic activation particular functional groups, as structural alerts toxicophores. able to covalently bind proteins macromolecules, causing cellular damage cell death. If adducted protein enzyme involved formation, time-dependent inhibition enzyme-also called mechanism-based (MBI) inactivation-can occur lead pharmacokinetic drug-drug interactions. To mitigate liabilities, common practice development includes avoiding assessing formation via trapping screens soft hard nucleophiles (glutathione, potassium cyanide, methoxylamine) microsomes. RM-positive derivatives further optimized afford candidates blocked minimized bioactivation potential. However, different still commonly used scaffolds design, structures. This review focuses on current state knowledge relations among structures, pathways, characterization, hepatotoxicity cytochrome P450 MBI vitro.