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

doi:10.3390/ijms19082367

Review

. 2018 Aug 11;19(8):2367.

doi: 10.3390/ijms19082367.

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

Klarissa D Jackson¹, Rebecca Durandis², Matthew J Vergne³

Affiliations

¹ College of Pharmacy and Health Sciences, Lipscomb University, Nashville, TN 37204, USA. klarissa.jackson@lipscomb.edu.
² College of Pharmacy and Health Sciences, Lipscomb University, Nashville, TN 37204, USA. rdurandis@mail.lipscomb.edu.
³ College of Pharmacy and Health Sciences, Lipscomb University, Nashville, TN 37204, USA. matt.vergne@lipscomb.edu.

PMID: 30103502
PMCID: PMC6121577
DOI: 10.3390/ijms19082367

Review

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

Klarissa D Jackson et al. Int J Mol Sci. 2018.

. 2018 Aug 11;19(8):2367.

doi: 10.3390/ijms19082367.

Authors

Klarissa D Jackson¹, Rebecca Durandis², Matthew J Vergne³

Affiliations

¹ College of Pharmacy and Health Sciences, Lipscomb University, Nashville, TN 37204, USA. klarissa.jackson@lipscomb.edu.
² College of Pharmacy and Health Sciences, Lipscomb University, Nashville, TN 37204, USA. rdurandis@mail.lipscomb.edu.
³ College of Pharmacy and Health Sciences, Lipscomb University, Nashville, TN 37204, USA. matt.vergne@lipscomb.edu.

PMID: 30103502
PMCID: PMC6121577
DOI: 10.3390/ijms19082367

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.

Keywords: bioactivation; cytochrome P450; hepatotoxicity; tyrosine kinase inhibitor.

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Conflict of interest statement

The authors declare no conflicts of interest.

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References

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[1] Cohen P. The origins of protein phosphorylation. Nat. Cell Biol. 2002;4:E127–E130. doi: 10.1038/ncb0502-e127. - DOI - PubMed

[2] Cohen P. The origins of protein phosphorylation. Nat. Cell Biol. 2002;4:E127–E130. doi: 10.1038/ncb0502-e127. - DOI - PubMed

[3] Krause D.S., Van Etten R.A. Tyrosine kinases as targets for cancer therapy. N. Engl. J. Med. 2005;353:172–187. doi: 10.1056/NEJMra044389. - DOI - PubMed

[4] Krause D.S., Van Etten R.A. Tyrosine kinases as targets for cancer therapy. N. Engl. J. Med. 2005;353:172–187. doi: 10.1056/NEJMra044389. - DOI - PubMed

[5] Cohen M.H., Williams G., Johnson J.R., Duan J., Gobburu J., Rahman A., Benson K., Leighton J., Kim S.K., Wood R., et al. Approval Summary for Imatinib Mesylate Capsules in the Treatment of Chronic Myelogenous Leukemia. Clin. Cancer Res. 2002;8:935–942. - PubMed

[6] Cohen M.H., Williams G., Johnson J.R., Duan J., Gobburu J., Rahman A., Benson K., Leighton J., Kim S.K., Wood R., et al. Approval Summary for Imatinib Mesylate Capsules in the Treatment of Chronic Myelogenous Leukemia. Clin. Cancer Res. 2002;8:935–942. - PubMed

[7] Wu P., Nielsen T.E., Clausen M.H. Small-molecule kinase inhibitors: An analysis of FDA-approved drugs. Drug Discov. Today. 2016;21:5–10. doi: 10.1016/j.drudis.2015.07.008. - DOI - PubMed

[8] Wu P., Nielsen T.E., Clausen M.H. Small-molecule kinase inhibitors: An analysis of FDA-approved drugs. Drug Discov. Today. 2016;21:5–10. doi: 10.1016/j.drudis.2015.07.008. - DOI - PubMed

[9] Liu S., Kurzrock R. Toxicity of targeted therapy: Implications for response and impact of genetic polymorphisms. Cancer Treat. Rev. 2014;40:883–891. doi: 10.1016/j.ctrv.2014.05.003. - DOI - PubMed

[10] Liu S., Kurzrock R. Toxicity of targeted therapy: Implications for response and impact of genetic polymorphisms. Cancer Treat. Rev. 2014;40:883–891. doi: 10.1016/j.ctrv.2014.05.003. - DOI - PubMed

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

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

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