Infigratinib Is a Reversible Inhibitor and Mechanism-Based Inactivator of Cytochrome P450 3A4

Tang, Lloyd Wei Tat; Teng, Jian Wei; Verma, Ravi Kumar; Koh, Siew Kwan; Zhou, Lei; Go, Mei‐Lin; Fan, Hao; Chan, Eric Chun Yong

doi:10.1124/dmd.121.000508

Cited by 19 publications

(24 citation statements)

References 46 publications

(57 reference statements)

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“…In gratiib(INF), a broblast growth factor receptor inhibitor, is being used in clinical studies for advanced cholangiocarcinoma. INF mediates inactivation of CYP3A4 by irreversible covalent addition of hemin and/or apoprotein, thereby exerting an inhibitory effect on cholangiocarcinoma 30 . FXR farnesoid x receptor also known as Nuclear Receptor Sub Family 1 Group H Member 4,NR1H4) is a nuclear receptor that can be activated by bile acid, and after activation, it can promote excretion of bile acid and inhibit uptake of bile acid in hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Bile metabolites as diagnostic biomarkers for perihilar cholangiocarcinoma

Zhang

Zhao

Sun

et al. 2022

Preprint

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It is difficult to directly obtain pathological diagnosis of perihilar cholangiocarcinoma (pCCA). Analysis of bile in the pCCA microenvironment, based on metabolomics and statistical methods, can help in clinical diagnosis. Clinical information, bile samples, blood liver function, blood CA199, CEA, and other indicators were collected from 33 patients with pCCA and 16 patients with gallstones. Bile samples were analyzed using non-targeted metabolomics methods, and a clinical diagnosis model was constructed using multivariate analysis technology. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and differential metabolite remodeling, we explored changes in the pCCA pathway and potential therapeutic targets. There were significant differences in patient blood TBIL, ALT, AST, TBA, CA19-9, and CEA indices (p<0.05, |log2(fc)|≥1) between two groups. A significant correlation was found between these different indicators by Spearman's analysis. The clinical parameters were correlated with mass-to-charge ratios of 305 (Positive Ion Mode, POS) and 246 (Negative Ion Mode, NEG) in the metabolic group (| r | ≥ 0.7, P ≤ 10–7). Cross-validation and external validation results showed that the recognition accuracy of the multivariate receiver-operating-characteristic (ROC) discriminant model for pCCA was 0.991 (POS) and 1 (NEG). The differential metabolites significantly affected bile secretion, cofactor biosynthesis, and amino-acid metabolism. Bile metabolomics combined with statistical analysis techniques can be used to accurately diagnose pCCA.

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Section: Discussionmentioning

confidence: 99%

Bile metabolites as diagnostic biomarkers for perihilar cholangiocarcinoma

Zhang

Zhao

Sun

et al. 2022

Preprint

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“…In our previous study, we established for the first time that INF reversibly inhibited and irreversibly inactivated CYP3A4-mediated rivaroxaban hydroxylation in a manner consistent with MBI (Tang et al, 2021b). However, it remained nebulous as to whether INF could also evoke inhibition and/or inactivation of CYP2J2-mediated metabolism of rivaroxaban.…”

Section: Introductionmentioning

confidence: 92%

“…, 2.5, 5, 7.5, 10, 15, 30, 45, 60, and 90 min), aliquots of each incubation mixture were withdrawn and added to an equal volume of ice-cold acetonitrile spiked with internal standard (0.1 µM erdafitinib) to stop the reaction. The samples were then centrifuged and assayed for the amount of unchanged INF remaining by UPLC-MS/MS as described in detail in our previous study (Tang et al, 2021b). Thereafter, aliquots of each primary incubation mixture were withdrawn and diluted 20-fold into the TDI secondary incubation mixture and incubated at 37°C for a further 30 min.…”

Section: Chemicals Andmentioning

confidence: 99%

“…To determine if the inactivation of CYP2J2 elicited by INF was reversible in vitro, we conducted an array of three complementary assays as described in many of our previous works (Tang et al, 2021a;Tang et al, 2021b;Tang et al, 2022). In the first series of experiments involving dialysis, primary incubation mixtures which comprised 20 pmol/mL rhCYP2J2, G6PDH, potassium phosphate buffer (0.1 M; pH 7.4) and INF (1 µM) were prepared, equilibrated and initiated with NADP+/G6P.…”

Section: Effect Of Dialysis On the Reversibility Of Inactivationmentioning

confidence: 99%

“…CYP2J2 TDI Assay. TDI assays were conducted as described in our previous works with minor modifications (Tang et al, 2021a;Tang et al, 2021b;Tang et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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Identification of Infigratinib as a Potent Reversible Inhibitor and Mechanism-Based Inactivator of CYP2J2: Nascent Evidence for a Potential In Vivo Metabolic Drug-Drug Interaction with Rivaroxaban

Tang

Chan

2022

J Pharmacol Exp Ther

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Infigratinib, a selective FGFR1‐3 tyrosine kinase inhibitor, alters dentoalveolar development at high doses

Michel

Aitken

Glover

et al. 2023

Developmental Dynamics

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BackgroundFibroblast growth factor receptor‐3 (FGFR3) gain‐of‐function mutations are linked to achondroplasia. Infigratinib, a FGFR1‐3 tyrosine kinase inhibitor, improves skeletal growth in an achondroplasia mouse model. FGFs and their receptors have critical roles in developing teeth, yet effects of infigratinib on tooth development have not been assessed. Dentoalveolar and craniofacial phenotype of Wistar rats dosed with low (0.1 mg/kg) and high (1.0 mg/kg) dose infigratinib were evaluated using micro‐computed tomography, histology, and immunohistochemistry.ResultsMandibular third molars were reduced in size and exhibited aberrant crown and root morphology in 100% of female rats and 80% of male rats at high doses. FGFR3 and FGF18 immunolocalization and extracellular matrix protein expression were unaffected, but cathepsin K (CTSK) was altered by infigratinib. Cranial vault bones exhibited alterations in dimension, volume, and density that were more pronounced in females. In both sexes, interfrontal sutures were significantly more patent with high dose vs vehicle.ConclusionsHigh dose infigratinib administered to rats during early stages affects dental and craniofacial development. Changes in CTSK from infigratinib in female rats suggest FGFR roles in bone homeostasis. While dental and craniofacial disruptions are not expected at therapeutic doses, our findings confirm the importance of dental monitoring in clinical studies.

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Infigratinib Is a Reversible Inhibitor and Mechanism-Based Inactivator of Cytochrome P450 3A4

Cited by 19 publications

References 46 publications

Bile metabolites as diagnostic biomarkers for perihilar cholangiocarcinoma

Bile metabolites as diagnostic biomarkers for perihilar cholangiocarcinoma

Identification of Infigratinib as a Potent Reversible Inhibitor and Mechanism-Based Inactivator of CYP2J2: Nascent Evidence for a Potential In Vivo Metabolic Drug-Drug Interaction with Rivaroxaban

Infigratinib, a selective FGFR1‐3 tyrosine kinase inhibitor, alters dentoalveolar development at high doses

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