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

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.

Download Full-text

The patient with renal cell cancer

10.1093/med/9780199592548.003.0172 ◽

2015 ◽

Author(s):

Tim Eisen

Keyword(s):

Tyrosine Kinase ◽

Cell Carcinoma ◽

Tyrosine Kinase Inhibitors ◽

Renal Cancer ◽

Renal Cell Cancer ◽

Renal Cell ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Cell Cancer

Renal cancer is the commonest malignancy of the kidney and worldwide, accounts for between 2% and 3% of the total cancer burden. The mainstay of curative treatment remains surgery. There have been significant advances in surgical technique, the most important ones being nephron-sparing surgery and laparoscopic nephrectomy. The medical treatment of advanced renal cell cancer has only improved markedly in the last decade with the development of antiangiogenic tyrosine-kinase inhibitors, inhibitors of mammalian target of rapamycin, and a diminished role for immunotherapy.Tyrosine-kinase inhibitor therapy results in reduction of tumour volume in around three-quarters of patients and doubles progression-free survival, but treatment is not curative. The management of side effects in patients on maintenance tyrosine-kinase inhibitors has improved in the last 3 years, although still presents difficulties which have to be actively considered.The molecular biology of renal cell carcinoma is better understood than for the majority of solid tumours. The commonest form of renal cancer, clear-cell carcinoma of the kidney, is strongly associated with mutations in the von Hippel–Lindau gene and more recently with chromatin-remodelling genes such as PBRM1. These genetic abnormalities lead to a loss of control of angiogenesis and uncontrolled proliferation of tumour cells. There is a very wide spectrum of tumour behaviour from the extremely indolent to the terribly aggressive. It is not currently known what accounts for this disparity in tumour behaviour.A number of outstanding questions are being addressed in scientific and clinical studies such as a clearer understanding of prognostic and predictive molecular biomarkers, the role of adjuvant therapy, the role of surgery in the presence of metastatic disease, how best to use our existing agents, and investigation of novel targets and therapeutic agents, especially novel immunotherapies.

Download Full-text

Molecularly targeted therapies in non-small cell lung cancer: The evolving role of tyrosine kinase inhibitors

Indian Journal of Cancer ◽

10.4103/ijc.ijc_449_19 ◽

2019 ◽

Vol 56 (5) ◽

pp. 23 ◽

Cited By ~ 2

Author(s):

DC Doval ◽

CJ Desai ◽

TP Sahoo

Keyword(s):

Lung Cancer ◽

Tyrosine Kinase ◽

Small Cell Lung Cancer ◽

Tyrosine Kinase Inhibitors ◽

Cell Lung Cancer ◽

Targeted Therapies ◽

Kinase Inhibitors ◽

Small Cell ◽

Small Cell Lung

Download Full-text

Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics andin vitroCYP2C9 activity

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155218801061 ◽

2018 ◽

Vol 25 (7) ◽

pp. 1599-1607 ◽

Cited By ~ 5

Author(s):

Makoto Hiraide ◽

Yuichi Minowa ◽

Yasuhiro Nakano ◽

Kenichi Suzuki ◽

Taro Shiga ◽

...

Keyword(s):

Cytochrome P450 ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

In Vitro Study ◽

International Normalized Ratio ◽

Bleeding Complications ◽

Cytochrome P450 2C9

BackgroundElevation of the international normalized ratio and bleeding complications has been reported in patients taking warfarin concomitantly with tyrosine kinase inhibitors such as gefitinib and erlotinib.ObjectiveTo assess the frequency, degree, and onset of international normalized ratio elevation in patients receiving warfarin with gefitinib or erlotinib, and changes in vitro cytochrome P450 2C9 activity.MethodsThis retrospective, single-center, observational study compared international normalized ratio values during the treatment with warfarin in the absence and presence of the tyrosine kinase inhibitors, gefitinib, and erlotinib. In addition, the inhibitory effect of tyrosine kinase inhibitors on cytochrome P450 2C9 activity was screened in an in vitro study.ResultsCompared with international normalized ratio at the baseline significant ( P < 0.05) international normalized ratio elevations were observed in the majority of the patients (5/6 patients with gefitinib, 83.3%; 6/7 patients with erlotinib, 85.7%) during concurrent therapy. The international normalized ratio was increased 1.8- and 1.6-fold relative to the baseline value, on median, in the presence of gefitinib and erlotinib, respectively, and the onset of international normalized ratio elevation was observed at a median of seven days and nine days, respectively. In vitro (S)-warfarin 7-hydroxylation activity was inhibited by 36% in the presence of 1 µM gefitinib and 27% by 10 µM erlotinib, which are comparable to the steady-state plasma levels of these tyrosine kinase inhibitors after standard dosing.ConclusionIn most patients, international normalized ratio elevation was observed within two weeks of the start of concomitant therapy with warfarin and gefitinib or erlotinib. To avoid excessive anticoagulant response by warfarin, international normalized ratio should be carefully monitored weekly and dosage adjustment of warfarin might be recommended during the first month after the start of concurrent tyrosine kinase inhibitor therapy.

Download Full-text

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

Era s journal of medical research ◽

10.24041/ejmr2020.34 ◽

2020 ◽

Vol 7 (2) ◽

pp. 205-211

Author(s):

Kaynat Fatima ◽

Syed Tasleem Raza ◽

Ale Eba ◽

Sanchita Srivastava ◽

Farzana Mahdi

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Protein Kinases ◽

Tyrosine Kinase Inhibitors ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Line Treatment ◽

First Line ◽

First Line Treatment

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

Download Full-text

Thrombotic microangiopathy in dasatinib-treated patients with chronic myeloid leukemia

Journal of Onco-Nephrology ◽

10.1177/2399369319887979 ◽

2019 ◽

Vol 4 (1-2) ◽

pp. 41-45 ◽

Cited By ~ 1

Author(s):

Takeo Koshida ◽

Sylvia Wu ◽

Hitoshi Suzuki ◽

Rimda Wanchoo ◽

Vanesa Bijol ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Tyrosine Kinase Inhibitors ◽

Thrombotic Microangiopathy ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Kidney Biopsy ◽

Kinase Inhibitor ◽

Target Effect

Dasatinib is the second-generation tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia. Proteinuria has been reported with this agent. We describe two kidney biopsy–proven cases of dasatinib-induced thrombotic microangiopathy that responded to stoppage of dasatinib and using an alternate tyrosine kinase inhibitor. Certain specific tyrosine kinase inhibitors lead to endothelial injury and renal-limited thrombotic microangiopathy. Hematologists and nephrologists need to be familiar with this off-target effect of dasatinib.

Download Full-text