Pathway-Dependent Inhibition of Paclitaxel Hydroxylation by Kinase Inhibitors and Assessment of Drug–Drug Interaction Potentials

2014 ◽  
Vol 42 (4) ◽  
pp. 782-795 ◽  
Author(s):  
Yedong Wang ◽  
Meiyu Wang ◽  
Huixin Qi ◽  
Peichen Pan ◽  
Tingjun Hou ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Kinase Inhibitors ◽  
Interaction Potentials ◽  
Dependent Inhibition ◽  
Drug Drug Interaction

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

2021 ◽  
Vol 22 ◽  
Author(s):  
Liyan Wang ◽  
Tingting Zhao ◽  
Yunxiang Wang ◽  
Banglian Hu ◽  
Jianfei Tao ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Cyp3a Activity ◽  
Drug Drug Interaction ◽  
Inhibitory Potential

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.

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

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

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.

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]

scholarly journals Isoniazid Mediates theCYP2B6*6Genotype-Dependent Interaction between Efavirenz and Antituberculosis Drug Therapy through Mechanism-Based Inactivation of CYP2A6

2014 ◽  
Vol 58 (7) ◽  
pp. 4145-4152 ◽  
Author(s):  
Michael H. Court ◽  
Fawziah E. Almutairi ◽  
David J. Greenblatt ◽  
Suwagmani Hazarika ◽  
Hongyan Sheng ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Plasma Concentrations ◽  
Liver Microsomes ◽  
Selective Inhibition ◽  
Recombinant Enzymes ◽  
Antituberculosis Drugs ◽  
Antituberculosis Therapy ◽  
Dependent Inhibition ◽  
Drug Drug Interaction

ABSTRACTEfavirenz is commonly used to treat patients coinfected with human immunodeficiency virus and tuberculosis. Previous clinical studies have observed paradoxically elevated efavirenz plasma concentrations in patients with theCYP2B6*6/*6genotype (but not theCYP2B6*1/*1genotype) during coadministration with the commonly used four-drug antituberculosis therapy. This study sought to elucidate the mechanism underlying this genotype-dependent drug-drug interaction.In vitrostudies were conducted to determine whether one or more of the antituberculosis drugs (rifampin, isoniazid, pyrazinamide, or ethambutol) potently inhibit efavirenz 8-hydroxylation by CYP2B6 or efavirenz 7-hydroxylation by CYP2A6, the main mechanisms of efavirenz clearance. Time- and concentration-dependent kinetics of inhibition by the antituberculosis drugs were determined using genotyped human liver microsomes (HLMs) and recombinant CYP2A6, CYP2B6.1, and CYP2B6.6 enzymes. Although none of the antituberculosis drugs evaluated at up to 10 times clinical plasma concentrations were found to inhibit efavirenz 8-hydroxylation by HLMs, both rifampin (apparent inhibition constant [Ki] = 368 μM) and pyrazinamide (Ki= 637 μM) showed relatively weak inhibition of efavirenz 7-hydroxylation. Importantly, isoniazid demonstrated potent time-dependent inhibition of efavirenz 7-hydroxylation in both HLMs (inhibitor concentration required for half-maximal inactivation [KI] = 30 μM; maximal rate constant of inactivation [kinact] = 0.023 min−1) and recombinant CYP2A6 (KI= 15 μM;kinact= 0.024 min−1) and also formed a metabolite intermediate complex consistent with mechanism-based inhibition. Selective inhibition of the CYP2B6.6 allozyme could not be demonstrated for any of the antituberculosis drugs using either recombinant enzymes orCYP2B6*6genotype HLMs. In conclusion, the results of this study identify isoniazid as the most likely perpetrator of this clinically important drug-drug interaction through mechanism-based inactivation of CYP2A6.

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