Cytochrome P450 Mediated Bioactivation of Saracatinib
- PMID: 27769111
- DOI: 10.1021/acs.chemrestox.6b00242
Cytochrome P450 Mediated Bioactivation of Saracatinib
Abstract
Saracatinib is a highly selective Src kinase inhibitor against all Src kinase family members and has demonstrated anticancer effects in preclinical models. Unfortunately, it has shown multiple adverse effects during its clinical trials, along with time-dependent inhibition of P450 enzymes. The major objective of this study was to identify reactive metabolites of saracatinib in vitro and in vivo. Four oxidative metabolites (M1-M4) were detected in rat and human liver microsomal incubation systems after exposure to saracatinib. An ortho-quinone-derived reactive metabolite existing as a GSH conjugate (M5) was found in microsomes fortified with GSH as a trapping agent. The formation of the metabolites detected was NADPH dependent. Metabolites M2-M4 were also observed in bile and urine of rats given saracatinib, and M5 was only detected in bile. Inhibition and recombinant P450 enzyme incubation studies demonstrated that P450 3A4 was the primary enzyme responsible for the metabolic activation of saracatinib. The metabolism study facilitates the understanding of correlation between saracatinib-induced hepatotoxicity and bioactivation.
Similar articles
-
Role of Cytochrome P450 Enzymes in the Metabolic Activation of Tyrosine Kinase Inhibitors.Int J Mol Sci. 2018 Aug 11;19(8):2367. doi: 10.3390/ijms19082367. Int J Mol Sci. 2018. PMID: 30103502 Free PMC article. Review.
-
Cytochrome P450 mediated metabolic activation of chrysophanol.Chem Biol Interact. 2018 Jun 1;289:57-67. doi: 10.1016/j.cbi.2018.04.015. Epub 2018 Apr 24. Chem Biol Interact. 2018. PMID: 29698620
-
LC-MS/MS reveals the formation of reactive ortho-quinone and iminium intermediates in saracatinib metabolism: Phase I metabolic profiling.Clin Chim Acta. 2018 Jul;482:84-94. doi: 10.1016/j.cca.2018.03.037. Epub 2018 Mar 31. Clin Chim Acta. 2018. PMID: 29614307
-
In Vitro and In Vivo Characterization of Reactive Intermediates of Corynoline.Drug Metab Dispos. 2015 Oct;43(10):1491-8. doi: 10.1124/dmd.115.065813. Epub 2015 Aug 10. Drug Metab Dispos. 2015. PMID: 26261285
-
Metabolic activation of drugs by cytochrome P450 enzymes: Biochemical insights into mechanism-based inactivation by fibroblast growth factor receptor inhibitors and chemical approaches to attenuate reactive metabolite formation.Biochem Pharmacol. 2022 Dec;206:115336. doi: 10.1016/j.bcp.2022.115336. Epub 2022 Nov 2. Biochem Pharmacol. 2022. PMID: 36332675 Review.
Cited by
-
Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress.Antioxidants (Basel). 2021 Dec 28;11(1):61. doi: 10.3390/antiox11010061. Antioxidants (Basel). 2021. PMID: 35052568 Free PMC article.
-
Dual Drug Repurposing: The Example of Saracatinib.Int J Mol Sci. 2024 Apr 22;25(8):4565. doi: 10.3390/ijms25084565. Int J Mol Sci. 2024. PMID: 38674150 Free PMC article. Review.
-
Differential Impact of Severity and Duration of Status Epilepticus, Medical Countermeasures, and a Disease-Modifier, Saracatinib, on Brain Regions in the Rat Diisopropylfluorophosphate Model.Front Cell Neurosci. 2021 Oct 15;15:772868. doi: 10.3389/fncel.2021.772868. eCollection 2021. Front Cell Neurosci. 2021. PMID: 34720886 Free PMC article.
-
Role of Cytochrome P450 Enzymes in the Metabolic Activation of Tyrosine Kinase Inhibitors.Int J Mol Sci. 2018 Aug 11;19(8):2367. doi: 10.3390/ijms19082367. Int J Mol Sci. 2018. PMID: 30103502 Free PMC article. Review.
-
Gut dysbiosis following organophosphate, diisopropylfluorophosphate (DFP), intoxication and saracatinib oral administration.Front Microbiomes. 2022;1:1006078. doi: 10.3389/frmbi.2022.1006078. Epub 2022 Oct 20. Front Microbiomes. 2022. PMID: 37304619 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous
