Role of Cytochrome P450 Enzymes in the Metabolic Activation of Tyrosine Kinase Inhibitors.

Klarissa D Jackson,Rebecca Durandis,Matthew J Vergne

doi:10.3390/ijms19082367

Klarissa D Jackson, Rebecca Durandis + Show 1 more

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https://doi.org/10.3390/ijms19082367

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Abstract

Tyrosine kinase inhibitors are a rapidly expanding class of molecular targeted therapies for the treatment of various types of cancer and other diseases. An increasing number of clinically important small molecule tyrosine kinase inhibitors have been shown to undergo cytochrome P450-mediated bioactivation to form chemically reactive, potentially toxic products. Metabolic activation of tyrosine kinase inhibitors is proposed to contribute to the development of serious adverse reactions, including idiosyncratic hepatotoxicity. This article will review recent findings and ongoing studies to elucidate the link between drug metabolism and tyrosine kinase inhibitor-associated hepatotoxicity.

Highlights

Improved understanding of the signaling pathways that regulate cellular functions, including growth and proliferation, has led to the identification of kinases as key drug targets [1]
Imatinib was the first successful small molecule tyrosine kinase inhibitor approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2001 for the treatment of chronic myeloid leukemia [3]
Several questions remain to establish the mechanistic link between reactive metabolites and drug toxicity: Does the tyrosine kinase inhibitor cause direct cellular toxicity and/or immune-mediated toxicity? What are the cellular targets and downstream mechanisms involved? Recent findings in the literature suggest that different tyrosine kinase inhibitors have different mechanisms of hepatotoxicity

Summary

Introduction

Improved understanding of the signaling pathways that regulate cellular functions, including growth and proliferation, has led to the identification of kinases as key drug targets [1]. Pharmacological inhibition of tyrosine kinases has been established as a clinically useful approach for the treatment of various types of cancer, and other diseases [2]. Small molecule kinase inhibitors are a rapidly growing class of targeted therapies, with the largest impact in cancer treatment. Imatinib was the first successful small molecule tyrosine kinase inhibitor approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2001 for the treatment of chronic myeloid leukemia [3]. Over 30 small molecule kinase inhibitors have been approved for clinical use in cancer therapy and other diseases (Table 1) [4]. The therapeutic indications for tyrosine kinase inhibitors include the treatment of several types of cancer, such as leukemia, lung, breast, kidney, gastrointestinal, and skin cancers.

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