Polymorphisms of CYP2D6 Gene and Gefitinib-Induced Hepatotoxicity

Takimoto, Takayuki; Kijima, Takashi; Otani, Yasushi; Nonen, Shinpei; Namba, Yoshinobu; Mori, Masahide; Yokota, Soichiro; Minami, Seigo; Komuta, Kiyoshi; Uchida, Junji; Imamura, Fumio; Furukawa, Mitsugi; Tsuruta, Naotoshi; Fujio, Yasushi; Azuma, Junichi; Tachibana, Isao; Kumanogoh, Atsushi

doi:10.1016/j.cllc.2013.03.003

Cited by 49 publications

(26 citation statements)

References 31 publications

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“…Takimoto et al 15 showed that coadministration of CYP3A4 inhibitors to patients with NSCLC and CYP2D6*5 Gefitinib Exposure and Related SNPs and *10 alleles might be associated with a greater risk of hepatotoxicity because 2 metabolic pathways of gefitinib were unavailable. In Asian populations, the frequency of the nonfunctional CYP2D6*5 allele is low.…”

Section: Introductionmentioning

confidence: 98%

Relationship Among Gefitinib Exposure, Polymorphisms of Its Metabolizing Enzymes and Transporters, and Side Effects in Japanese Patients With Non–Small-Cell Lung Cancer

Kobayashi

Sato

Niioka

et al. 2015

Clinical Lung Cancer

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Section: Introductionmentioning

confidence: 98%

Relationship Among Gefitinib Exposure, Polymorphisms of Its Metabolizing Enzymes and Transporters, and Side Effects in Japanese Patients With Non–Small-Cell Lung Cancer

Kobayashi

Sato

Niioka

et al. 2015

Clinical Lung Cancer

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“…It has been shown in a retrospective study that CYP2D6 genotype alone made no difference in higher risk of hepatotoxicity, however, patients harboring the allele *5 and *10 of CYP2D6 gene were classified as intermediate or poor metabolizers and were more vulnerable to recurrent and severe hepatotoxicity with gefitinib treatment [84]. Besides, gefitinib-related hepatotoxicity is more common in Asians than non-Asians, which may also result from CYP polymorphisms among different ethnic groups [85, 86]. …”

Section: Hepatotoxicity Of Tkis: An Inevitable Issue Limiting Their Cmentioning

confidence: 99%

Tyrosine kinase inhibitors: friends or foe in treatment of hepatic fibrosis?

Liu

Lin

et al. 2016

Oncotarget

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Aberrant activity of tyrosine kinases has been proved to be associated with multiple diseases including fibrotic diseases. Tyrosine kinases inhibitors (TKIs) might be a novel approach to transform the anti-fibrotic treatment. However, both beneficial and adverse effects are observed by researchers when using these TKIs in either preclinical animal models or patients with hepatic fibrosis. Since hepatotoxicity of TKIs is the leading cause for drug withdrawals thus limits its application in anti-fibrosis, not only efficacy but also safety of TKIs should be paid great concerns. It has been observed in a few studies that TKIs could induce relatively high rate of hepatic biochemical markers elevations and even result in liver failure. Fortunately, several strategies have been adopt to handle with the hepatotoxicity. Accumulating evidences suggest that hepatic stellate cells (HSC) play a pivotal role in hepatic fibrogenesis, so it might be a good option to develop selective TKIs specifically targeting HSCs. The present review will briefly summarize the anti-fibrotic mechanism of TKIs, adverse effects of TKIs as well as the novel developed selective delivery of TKIs.

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“…13 Previous studies indicate that among gefitinib metabolites, only O -desmethyl gefitinib can be identified in human plasma, whereas the plasma concentrations of other gefitinib metabolites, such as M537194 and M387783, which are metabolized by CYP3A4 are very low or even undetectable 2,13–16. There are several studies showing that patients with poor metabolizers (PMs) of CYP2D6 and inhibition of CYP3A4 may lead to prominent overdose of gefitinib, which may finally cause gefitinib-induced hepatotoxicity 13,16. Therefore, we believe that it is necessary to evaluate the effects of 24 CYP2D6 variants on the metabolism of gefitinib in vitro.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of wild-type and 24 CYP2D6 allelic variants on gefitinib metabolism in vitro

Fang

Zheng

et al. 2017

DDDT

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BackgroundCytochrome P450 2D6 (CYP2D6), a member of the CYP450 enzyme super family, is a polymorphic enzyme that metabolizes ~25% of therapeutic drugs. CYP2D6 exhibits significant genetic polymorphisms which might cause adverse effects and therapeutic failures of some drugs.ObjectiveThe purpose of this study was to evaluate the catalytic activities of 22 novel CYP2D6 alleles (CYP2D6*87, *88, *89, *90, *91, *92, *93, *94, *95, *96, *97, *98, R25Q, F164L, E215K, F219S, V327M, D336N, V342M, R344Q, R440C, R497C) on the metabolism of gefitinib in vitro.Methods and resultsCYP2D6 variants were incubated with 1–100 μM gefitinib for 60 min at 37°C and the reaction was terminated by cooling to −80°C immediately. Gefitinib and its metabolite O-desmethyl gefitinib were analyzed by an ultra-performance liquid chromatography-tandem mass spectrometry system. Compared to CYP2D6.1, most CYP2D6 variants exhibited significantly decreased relative clearance values (from 3.11% to 79.35%), whereas CYP2D6.92 and CYP2D6.96 displayed no detectable enzyme activity. Only CYP2D6.94 exhibited a markedly increased intrinsic clearance value, and eight variants (CYP2D6.88, CYP2D6.89, CYP2D6.91, CYP2D6.97, V342M, R344Q, F219S, and F164L) showed no significant difference. In addition, 23 CYP2D6 allelic isoforms exhibited substrate inhibition trend toward gefitinib.ConclusionAs the first study of all the aforementioned alleles for gefitinib metabolism, these comprehensive data may help in the clinical assessment of the metabolism of gefitinib, and may also offer a reference for personalized treatment with gefitinib in clinical settings.

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Polymorphisms of CYP2D6 Gene and Gefitinib-Induced Hepatotoxicity

Cited by 49 publications

References 31 publications

Relationship Among Gefitinib Exposure, Polymorphisms of Its Metabolizing Enzymes and Transporters, and Side Effects in Japanese Patients With Non–Small-Cell Lung Cancer

Relationship Among Gefitinib Exposure, Polymorphisms of Its Metabolizing Enzymes and Transporters, and Side Effects in Japanese Patients With Non–Small-Cell Lung Cancer

Tyrosine kinase inhibitors: friends or foe in treatment of hepatic fibrosis?

Functional characterization of wild-type and 24 CYP2D6 allelic variants on gefitinib metabolism in vitro

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