In Vitro Assessment of Time-Dependent Inhibitory Effects on CYP2C8 and CYP3A Activity by Fourteen Protein Kinase Inhibitors

Filppula, Anne M.; Neuvonen, Pertti J.; Backman, Janne T.

doi:10.1124/dmd.114.057695

Cited by 58 publications

(89 citation statements)

References 52 publications

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“…Recent studies indicate that many tyrosine kinase inhibitors cause time-dependent inhibition of cytochrome P450 enzymes, particularly CYP3A, in vitro [26]. Mechanism based-inactivation of CYP3A has been characterized for dasatinib [15], lapatinib [18,29], axitinib [21], lestaurtinib, and saracatinib [30]. …”

Section: Bioactivation Of Small Molecule Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

“…In another study, Filppula et al screened 14 kinase inhibitors for time-dependent inhibition of CYP3A and CYP2C8 [30]. Amodiaquine N -deethylation was used as the marker reaction for CYP2C8 activity, and midazolam 1’-hydroxylation was used as the marker for CYP3A activity in human liver microsomes [30].…”

Section: Bioactivation Of Small Molecule Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

“…Amodiaquine N -deethylation was used as the marker reaction for CYP2C8 activity, and midazolam 1’-hydroxylation was used as the marker for CYP3A activity in human liver microsomes [30]. Time-dependent inhibition was assessed by IC 50 shift assay with the 14 kinase inhibitors.…”

Section: Bioactivation Of Small Molecule Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

“…Detailed mechanism-based inactivation was characterized for bosutinib, lestaurtinib, and saracatinib. Erlotinib and gefitinib were found to activate/stimulate midazolam 1′-hydroxylation in experiments without pre-incubation [30]. Bosutinib was found to cause time-dependent inhibition of CYP2C8-mediated amodiaquine N -deethylation (“weak mechanism-based inactivation”), and lestaurtinib and saracatinib were found to cause time-dependent inhibition (mechanism-based inactivation) of CYP3A-mediated midazolam 1′-hydroxylation [30].…”

Section: Bioactivation Of Small Molecule Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

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

Jackson

Durandis

2018

IJMS

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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.

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Section: Bioactivation Of Small Molecule Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Section: Bioactivation Of Small Molecule Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Section: Bioactivation Of Small Molecule Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Section: Bioactivation Of Small Molecule Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

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

Jackson

Durandis

2018

IJMS

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“…Therefore, its bioavailability is influenced by the activity of the excretory transporters ABCB1 and ABCG2 in the small-intestinal mucosa (Hu et al 2009;Gnoth et al 2010). In addition, sorafenib is primarily metabolized by cytochrome P450 3A4 (CYP3A4) in the small-intestinal mucosa or the liver, and it is also subjected to glucuronidation mediated by uridine diphosphate glucuronosyl transferase (UGT) 1A9 (Lathia et al 2006;Peer et al 2012;Filppula et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Monitoring Serum Levels of Sorafenib and Its <i>N</i>-Oxide Is Essential for Long-Term Sorafenib Treatment of Patients with Hepatocellular Carcinoma

Shimada

Okawa

Kondo

et al. 2015

Tohoku J. Exp. Med.

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Sorafenib, an oral multi-kinase inhibitor, is the final therapy prior to palliative care for advanced hepatocellular carcinoma (HCC). However, due to its adverse effects, 20% of patients must discontinue sorafenib within 1 month after first administration. To identify ways to predict the adverse effects and administer the drug for longer periods, we explored the relationship between the duration of sorafenib treatment and the pharmacokinetics of sorafenib and its major metabolite, sorafenib N-oxide. Twenty-five subjects enrolled in the study were divided into two groups: patients with dosage reduced or withdrawn due to adverse effects (n = 8), and patients with dosage maintained for 1 month after initial administration (n = 17). We evaluated early sorafenib accumulation as the area under the curve of sorafenib and sorafenib N-oxide concentrations during days 1-7 (AUC sorafenib and AUC N-oxide , respectively). Inter-group comparison revealed that AUC N-oxide and AUC ratio (AUC N-oxide /AUC sorafenib ) were significantly higher in the dosage reduction/withdrawal group (P = 0.031 and P = 0.0022, respectively). Receiver operating characteristic analysis indicated that AUC N-oxide and AUC ratio were reliable predictors of adverse effects. When patients were classified by cut-off points (AUC N-oxide : 2.0 μg•day/mL, AUC ratio: 0.13), progression-free survival was significantly longer in patients with AUC N-oxide ≤ 2.0 μg•day/mL (P = 0.0048, log-rank test). In conclusion, we recommend to simultaneously monitor serum levels of sorafenib and its N-oxide during the early stage after the first administration, which enables us to provide safe and long-term therapy for each HCC patient with sorafenib.

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Target Enzyme‐Activated Two‐Photon Fluorescent Probes: A Case Study of CYP3A4 Using a Two‐Dimensional Design Strategy

Ning

Wang

et al. 2019

Angewandte Chemie

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The rapid development of fluorescent probes for monitoring target enzymes is still agreat challenge owingtothe lacko fe fficient ways to optimizeaspecific fluorophore. Herein, ap ractical two-dimensional strategy was designed for the development of an isoform-specific probe for CYP3A4, ak ey cytochrome P450 isoform responsible for the oxidation of most clinical drugs.Infirst dimension of the design strategy, ap otential two-photon fluorescent substrate (NN)f or CYP3A4 was effectively selected using ensemble-based virtual screening.Inthe second dimension, various substituent groups were introduced into NN to optimize the isoform-selectivity and reactivity.F inally,w ith ideal selectivity and sensitivity, NEN was successfully applied to the real-time detection of CYP3A4 in living cells and zebrafish. These findings suggested that our strategy is practical for developing an isoform-specific probe for atarget enzyme.Cytochrome P450 monooxygenase (CYP) is as uperfamily of oxidative enzymes that metabolizes thousands of endogenous and exogenous substances through alkyl carbon and aromatic ring hydroxylation, O-a nd N-dealkylation, and epoxidation. [1] CYP3A4 is regarded as the most important CYP isoform in humans owing to its high abundance in liver and broad substrate spectrum, which contributes to the metabolism of more than 50 %o fclinical drugs. [2,3] Unfortunately,C YP3A4 activity can be modulated by many clinical drugs,t hereby frequently causing unfavorable drug-drug interactions (DDI), further leading to altered clinical outcomes or even life-threatening adverse reactions. [4] Additionally,asignificant inter-individual variability of CYP3A4 activity is frequently reported, arising from an umber of sources including genetic polymorphism and the response to environmental influences. [5] These factors have greatly limited the understanding of the precise role of CYP3A4 in drug metabolism and DDI, as aresult, negatively impacted clinical medication safety and effectiveness.To accurately characterize CYP3A4 activity,s ensitive technologies capable of the real-time monitoring of CYP3A4 activity are urgently needed. Tr aditional detection methods mainly rely upon mass spectrometry or high-performance liquid chromatography, [6,7] which are not compatible with living cell or in vivo applications.T wo-photon (TP) fluorescence microscopy,byvirtue of its higher sensitivity,real-time high spatial resolution imaging,a nd amenability to deeptissue bioimaging,h as shed new light on the monitoring of target enzyme activity in complex systems. [8, 9] However,n o TP fluorescent probe has been developed for the real-time and selective imaging of endogenous CYP3A4 activity in living systems.Previous attempts to develop af luorescent probe for CYP3A4 were based on adealkylation mechanism to release ad etectable moiety.T he O-alkyl derivatives of coumarin, resorufin, and fluorescein were designed and synthesized but met with limited success in isoform selectivity. [10] Theleading cause for the poor specificity of these probes is th...

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In Vitro Assessment of Time-Dependent Inhibitory Effects on CYP2C8 and CYP3A Activity by Fourteen Protein Kinase Inhibitors

Cited by 58 publications

References 52 publications

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

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

Monitoring Serum Levels of Sorafenib and Its <i>N</i>-Oxide Is Essential for Long-Term Sorafenib Treatment of Patients with Hepatocellular Carcinoma

Target Enzyme‐Activated Two‐Photon Fluorescent Probes: A Case Study of CYP3A4 Using a Two‐Dimensional Design Strategy

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