Effect of CYP3A4 inducer dexamethasone on hepatotoxicity of lapatinib: clinical and in vitro evidence

被引:0
作者
Yi Ling Teo
Manit Saetaew
Suthan Chanthawong
Yoon Sim Yap
Eric Chun Yong Chan
Han Kiat Ho
Alexandre Chan
机构
[1] National University of Singapore,Department of Pharmacy, Faculty of Science
[2] Ubon Ratchathani University,Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences
[3] Khon Kaen University,Clinical Pharmacy Division, Faculty of Pharmaceutical Sciences
[4] National Cancer Centre Singapore,Department of Medical Oncology
[5] Department of Oncology Pharmacy,undefined
[6] National Cancer Centre Singapore,undefined
来源
Breast Cancer Research and Treatment | 2012年 / 133卷
关键词
Cell viability; CYP3A4; Dexamethasone; Drug–drug interaction; Hepatotoxicity; Lapatinib;
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暂无
中图分类号
学科分类号
摘要
Concomitant usage of lapatinib, a cytochrome P450 (CYP) 3A4 substrate and dexamethasone, a CYP3A4 inducer, is a pharmacokinetic drug–drug interaction. This combination may increase the formation of reactive lapatinib metabolites, which is potentially hepatotoxic. This study aims to evaluate the clinical effect of dexamethasone on incidence of hepatotoxicity and to ascertain its in vitro role using a parallel cell culture model experimental setup. Clinical effects of dexamethasone on lapatinib-induced hepatotoxicity were evaluated in a nested case–control study based on 120 patient data obtained from our records. For the in vitro experiment, metabolically competent transforming growth factor α mouse hepatocytes (TAMH) were treated with lapatinib and viabilities were compared in the presence or absence of dexamethasone. After adjusting for confounders, patients receiving the combination were 4.57 times (95% CI 1.23–16.88, p = 0.02) more likely to develop hepatotoxicity and 3.48 times (95% CI 1.24–9.80, p = 0.02) more likely to develop a clinically important change in alanine aminotransferase than compared to the other group. Treatment of TAMH cells with lapatinib and dexamethasone caused a further reduction in viability, as compared to treatment with lapatinib alone. At 5 μM lapatinib, the introduction of dexamethasone 20 μM produced a 59% decline in viability. This is the first study to document a clinically important interaction between lapatinib and dexamethasone, which associates with an increased occurrence of hepatotoxicity. The in vitro findings have provided substantiating evidence and insights on the role of dexamethasone in lapatinib-induced hepatotoxicity.
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页码:703 / 711
页数:8
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