ArticleChemical research in toxicology2018
Identification of Novel Pathways in Idelalisib Metabolism and Bioactivation.
Article in Chemical research in toxicology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
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- Cytochrome P450-mediated metabolism of K31, a Ko143-derived ATP-binding cassette subfamily G member 2 inhibitor.Drug metabolism and disposition: the biological fate of chemicals · 2026Article
- A renaissance in targeting the PI3K/AKT/mTOR pathway.Nature reviews. Drug discovery · 2026Review
- Role of metabolites in drug-drug interactions.Drug metabolism and pharmacokinetics · 2026Review
- Orbitrap HRMS-Based Comprehensive Metabolite Characterization of Duvelisib in Cross-Species Hepatocytes.Rapid communications in mass spectrometry : RCM · 2026Article
- Quinazolinone derivatives as potential anti‑tumor agents: Structural features and molecular mechanisms in inducing cell death (Review).International journal of molecular medicine · 2025Review
- Inhibition of heme-thiolate monooxygenase CYP1B1 prevents hepatic stellate cell activation and liver fibrosis by accumulating trehalose.Science translational medicine · 2024Article
- Sulfation of chondroitin and bile acids converges to antagonize Wnt/Acta pharmaceutica Sinica. B · 2024Article
- Non-Clinical Toxicology Evaluation of the Novel Non-ATP Competitive Oral PI3 Kinase Delta Inhibitor Roginolisib.International journal of toxicology · 2023Article
- IOA-244 is a Non-ATP-competitive, Highly Selective, Tolerable PI3K Delta Inhibitor That Targets Solid Tumors and Breaks Immune Tolerance.Cancer research communications · 2023Article
- Bi-allelic hydroxymethylbilane synthase inactivation defines a homogenous clinico-molecular subtype of hepatocellular carcinoma.Journal of hepatology · 2022Article
- Role of CYP2A6 in Methimazole Bioactivation and Hepatotoxicity.Chemical research in toxicology · 2021Article
- PI3K inhibitors are finally coming of age.Nature reviews. Drug discovery · 2021Review
- Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitors.Cell reports · 2021Article
- Cell Type-Specific Roles of CD38 in the Interactions of Isoniazid with NADDrug metabolism and disposition: the biological fate of chemicals · 2020Article
- ABCG2 Deficiency Does Not Alter Dolutegravir Metabolism and Pharmacokinetics.The Journal of pharmacology and experimental therapeutics · 2020Article
- 1-(Benzo[b]thiophen-4-yl)piperazine Ring Induced Bioactivation of Brexpiprazole in Liver Microsomes: Identification and Characterization of Reactive Conjugates Using Ultra-High-Performance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry.European journal of drug metabolism and pharmacokinetics · 2020Article
- Dual functional immunostimulatory polymeric prodrug carrier with pendent indoximod for enhanced cancer immunochemotherapy.Acta biomaterialia · 2019Article
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Authors and funding
6 authors.
Funding
Abstract
Idelalisib (ILB) is a selective phosphatidylinositol-3-kinase delta inhibitor approved for the treatment of hematological malignancies. However, ILB frequently causes hepatotoxicity, and the exact mechanism remains unclear. The current study profiled the metabolites of ILB in mouse liver, urine, and feces. The major metabolites found in the liver were oxidized metabolite GS-563117 (M1) and ILB-glutathione (GSH) adduct (M2). These metabolic pathways were confirmed by analysis of urine and feces from mice treated with ILB. Identification of ILB-GSH adduct (M2) suggests the formation of reactive metabolites of ILB. We also found that M1 can produce reactive metabolites and form M1-GSH adducts. The GSH-conjugates identified in mouse liver were also found in the incubations of ILB and M1 with human liver microsomes. Furthermore, we illustrated that CYP3A4 and 2C9 are the key enzymes contributing to the bioactivation pathway of ILB and M1. In summary, our work revealed that both ILB and its major metabolite M1 can undergo bioactivation to produce reactive metabolites in the liver. Further studies are required to determine whether these metabolic pathways contribute to ILB hepatotoxicity.
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