In vitro Measurement and In vivo Prediction of Time-Dependent Inhibitory Effects of Three Tyrosine Kinase Inhibitors on CYP3A Activity

Background: Imatinib, sunitinib, and gefitinib are the three most common tyrosine kinase inhibitors (TKIs). However, their quantitative drug-drug interaction potentials In vivo and the relationship between their structure and inhibitory activity remain unknown. Objective: This study aimed to investigate the potential drug-drug interaction risk of three TKIs based on CYP3A. Methods: 6β-Hydroxylated testosterone formation was selected to probe the CYP3A activity in human liver microsomes. Molecular docking simulation was performed to explore the potential structural alerts. Results: Imatinib exhibited the strongest inhibitory effect towards CYP3A, while the inhibitory potential of gefitinib and sunitinib were comparable to each other but weaker than imatinib. IC50 shift assays demonstrated that the inhibitory potential of all three TKIs was significantly increased after a 30-min preincubation with NADPH. The KI and Kinact values of imatinib, sunitinib, and gefitinib were 3.75 μM and 0.055 min–1, 1.96 μM and 0.037 min–1, and 9.94 μM and 0.031 min–1, respectively. IVIVE results showed that there was a 1.3- to 43.1-fold increase in the AUC of CYP3A-metabolizing drugs in the presence of the TKIs. Conclusion: All three TKIs exhibited a typical irreversible inhibitory effect towards CYP3A. The presence of more N-heterocycles and the resulting better binding confirmation of imatinib may have been responsible for its stronger inhibitory effect than sunitinib and gefitinib. Therefore, caution should be taken when CYP3A-metabolizing drugs are co-administrated with imatinib, sunitinib, or gefitinib.

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Tyrosine kinase inhibitors and acid-inhibitory drugs: Strong concomitant dispensing and drug-drug interaction risk

Annals of Oncology ◽

10.1093/annonc/mdy303.027 ◽

2018 ◽

Vol 29 ◽

pp. viii658

Author(s):

F. Grude ◽

C. Vigneau-Victorri ◽

D. Deniel Lagadec ◽

E. Michaud ◽

H. Bourgeois ◽

...

Keyword(s):

Drug Interaction ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Drug Drug Interaction

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Prevalence of the concurrent administration of contraindicated medications in patients with cancer treated with tyrosine kinase inhibitors (TKIs): A pilot study from the IU Simon Comprehensive Cancer Center.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e18714 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e18714-e18714

Author(s):

Dana Alhaffar ◽

Yan Han ◽

Julianne Darling ◽

Todd C. Skaar ◽

Christopher A. Fausel ◽

...

Keyword(s):

Drug Interaction ◽

Tyrosine Kinase ◽

Drug Interactions ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Comprehensive Cancer Center ◽

Cancer Center ◽

Concurrent Administration ◽

Patients With Cancer ◽

Drug Drug Interaction

e18714 Background: Polypharmacy may result in drug-drug interactions that reduce efficacy or increase toxicities to patients. Tyrosine kinase inhibitors (TKIs), which is standard therapy for many patients with cancer, have interactions with many commonly prescribed drugs (including proton pump inhibitors [PPIs] and cytochrome inhibitors/inducers) which alter their metabolism. Methods: Retrospective study of 100 consecutively chosen patients with advanced cancer treated with TKIs were identified. Patients < 18 years of age, participating in clinical trials, or taking an investigational treatment for their cancer were excluded. TKI start date and concurrent medications were identified from chart reviews. Documentation was undertaken to record co-administration of drugs that could prolong QT interval, PPIs, and CYP3A inhibitors and inducers. QT prolonging medications were divided into those with known risk (KR), conditional risk (CR), and probable risk (PR). IUSM Clinical Pharmacology Flockhart table was utilized for cytochrome drug interactions. All three categories of cytochrome inhibitors (strong, moderate, and weak) were included in the analysis. The primary objective was to estimate the percentage of patients treated with TKIs co-administered these classes of drugs with a potential for harmful drug-drug interaction. Results: Median age of 100 pts was 57 and median duration of treatment with the TKI was 441 days. 85 of 100 pts receiving TKIs for their cancer were also prescribed at least 1 drug with the potential for drug-drug interaction, including 39 with a QT prolonging drug with known risk and 25 with a CYP3A inducer or inhibitor. 53% had documentation of EKG while on TKI treatment. Conclusions: Most patients in this chart review were co-administered TKIs with other agents with a potential for harmful drug-drug interactions. Continual monitoring of medications is necessary to optimize efficacy of TKIs and reduce the chance for harmful side effects.[Table: see text]

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Drug-Drug Interaction Potentials of Tyrosine Kinase Inhibitors via Inhibition of UDP-Glucuronosyltransferases

Scientific Reports ◽

10.1038/srep17778 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 22

Author(s):

Nan Zhang ◽

Yong Liu ◽

Hyunyoung Jeong

Keyword(s):

Drug Interaction ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Interaction Potentials ◽

Drug Drug Interaction

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Tyrosine kinase inhibitors (TKI): Awareness of drug-drug interaction

Annals of Oncology ◽

10.1093/annonc/mdx375.014 ◽

2017 ◽

Vol 28 ◽

pp. v399

Author(s):

N. Ozdemir ◽

S. Toptas ◽

M.A.N. Sendur ◽

O. Yazici ◽

B. Öksüzoğlu ◽

...

Keyword(s):

Drug Interaction ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Drug Drug Interaction

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In vitro study on the effect of cornin on the activity of cytochrome P450 enzymes

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03309-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Qun Zhang ◽

Zengqiang Qu ◽

Yanqing Zhou ◽

Jin Zhou ◽

Junwei Yang ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Interaction ◽

Liver Microsomes ◽

In Vitro Study ◽

Inhibitory Effect ◽

Dependent Manner ◽

Cytochrome P450 Enzymes ◽

Drug Drug Interaction ◽

Dose Dependent

Abstract Background Cornin is a commonly used herb in cardiology for its cardioprotective effect. The effect of herbs on the activity of cytochrome P450 enzymes (CYP450s) can induce adverse drug-drug interaction even treatment failure. Therefore, it is necessary to investigate the effect of cornin on the activity of CYP450s, which can provide more guidance for the clinical application of cornin. Methods Cornin (100 μM) was incubated with eight isoforms of CYP450s, including CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1, in pooled human liver microsomes. The inhibition model and corresponding parameters were also investigated. Results Cornin exerted significant inhibitory effect on the activity of CYP3A4, 2C9, and 2E1 in a dose-dependent manner with the IC50 values of 9.20, 22.91, and 14.28 μM, respectively (p < 0.05). Cornin inhibited the activity of CYP3A4 non-competitively with the Ki value of 4.69 μM, while the inhibition of CYP2C9 and 2E1 by cornin was competitive with the Ki value of 11.31 and 6.54 μM, respectively. Additionally, the inhibition of CYP3A4 by cornin was found to be time-dependent with the KI/Kinact value of 6.40/0.055 min− 1·μM− 1. Conclusions The inhibitory effect of cornin on the activity of CYP3A4, 2C9, and 2E1 indicated the potential drug-drug interaction between cornin and drugs metabolized by these CYP450s, which needs further investigation and validation.

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Inhibitory Effect of Tyrosine Kinase Inhibitors on Antigen-Induced Tracheal Contraction and Histamine Release in Guinea Pigs

International Archives of Allergy and Immunology ◽

10.1159/000237380 ◽

1996 ◽

Vol 111 (3) ◽

pp. 291-298

Author(s):

Hajime Iwagoe ◽

Hirotsugu Kohrogi ◽

Kazuhiko Fujii ◽

Junji Hamamoto ◽

Nahomi Hirata ◽

...

Keyword(s):

Tyrosine Kinase ◽

Histamine Release ◽

Tyrosine Kinase Inhibitors ◽

Guinea Pigs ◽

Kinase Inhibitors ◽

Inhibitory Effect

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MEK inhibition enhances the response to tyrosine kinase inhibitors in acute myeloid leukemia

Scientific Reports ◽

10.1038/s41598-019-54901-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

María Luz Morales ◽

Alicia Arenas ◽

Alejandra Ortiz-Ruiz ◽

Alejandra Leivas ◽

Inmaculada Rapado ◽

...

Keyword(s):

Drug Resistance ◽

Acute Myeloid Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Resistance Pathway ◽

Acute Myeloid

AbstractFMS-like tyrosine kinase 3 (FLT3) is a key driver of acute myeloid leukemia (AML). Several tyrosine kinase inhibitors (TKIs) targeting FLT3 have been evaluated clinically, but their effects are limited when used in monotherapy due to the emergence of drug-resistance. Thus, a better understanding of drug-resistance pathways could be a good strategy to explore and evaluate new combinational therapies for AML. Here, we used phosphoproteomics to identify differentially-phosphorylated proteins in patients with AML and TKI resistance. We then studied resistance mechanisms in vitro and evaluated the efficacy and safety of rational combinational therapy in vitro, ex vivo and in vivo in mice. Proteomic and immunohistochemical studies showed the sustained activation of ERK1/2 in bone marrow samples of patients with AML after developing resistance to FLT3 inhibitors, which was identified as a common resistance pathway. We examined the concomitant inhibition of MEK-ERK1/2 and FLT3 as a strategy to overcome drug-resistance, finding that the MEK inhibitor trametinib remained potent in TKI-resistant cells and exerted strong synergy when combined with the TKI midostaurin in cells with mutated and wild-type FLT3. Importantly, this combination was not toxic to CD34+ cells from healthy donors, but produced survival improvements in vivo when compared with single therapy groups. Thus, our data point to trametinib plus midostaurin as a potentially beneficial therapy in patients with AML.

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