ArticleInvestigational new drugs2021
Extrahepatic metabolism of ibrutinib.
Article in Investigational new drugs, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
7 citing papers in PubMed, 27 citations in OpenAlex.
- Redox destabilization by ibrutinib promotes ferroptosis in diffuse large B-cell lymphoma (DLBCL).Cell death discovery · 2025Article
- Influence of CYP2D6, CYP3A, and ABCG2 Genetic Polymorphisms on Ibrutinib Disposition in Chinese Healthy Subjects.Pharmaceuticals (Basel, Switzerland) · 2025Article
- COOKIE-Pro: covalent inhibitor binding kinetics profiling on the proteome scale.Nature communications · 2025Article
- Pharmacogenetic Biomarkers of Ibrutinib Response and Toxicity in Chronic Lymphocytic Leukemia: Insights from an Observational Study.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Glutathione dynamics in subcellular compartments and implications for drug development.Current opinion in chemical biology · 2024Review
- Biotransformation novel advances - 2021 year in review.Drug metabolism reviews · 2022Review
- A High-Throughput Clinical Laboratory Methodology for the Therapeutic Monitoring of Ibrutinib and Dihydrodiol Ibrutinib.Molecules (Basel, Switzerland) · 2022Article
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ibrutinib is a first-in-class Bruton's kinase inhibitor used in the treatment of multiple lymphomas. In addition to CYP3A4-mediated metabolism, glutathione conjugation can be observed. Subsequently, metabolism of the conjugates and finally their excretion in feces and urine occurs. These metabolites, however, can reach substantial concentrations in human subjects, especially when CYP3A4 is inhibited. Ibrutinib has unexplained nephrotoxicity and high metabolite concentrations are also found in kidneys of Cyp3a knockout mice. Here, a mechanism is proposed where the intermediate cysteine metabolite is bioactivated. The metabolism of ibrutinib through this glutathione cycle was confirmed in cultured human renal proximal tubule cells. Ibrutinib-mediated toxicity was enhanced in-vitro by inhibitors of breast cancer resistance protein (BCRP), P-glycoprotein (P-gp) and multidrug resistance protein (MRP). This was a result of accumulating cysteine metabolite levels due to efflux inhibition. Finally, through inhibition of downstream metabolism, it was shown now that direct conjugation was responsible for cysteine metabolite toxicity.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.