Extrahepatic metabolism of ibrutinib

Male Cell Survival Antineoplastic Agents Kidney Tubules, Proximal Mice 03 medical and health sciences SDG 3 - Good Health and Well-being Piperidines ATP Binding Cassette Transporter, Subfamily G, Member 2 Animals Cytochrome P-450 CYP3A Humans Pharmacology (medical) Pharmacokinetics ATP Binding Cassette Transporter, Subfamily B, Member 1 LC-MS/MS Cells, Cultured Aged Pharmacology Mice, Knockout Preclinical Studies 0303 health sciences Bioactivation Adenine Ibrutinib Acute Kidney Injury Glutathione Neoplasm Proteins 3. Good health Metabolism Oncology Glutathione cycle Multidrug Resistance-Associated Proteins
DOI: 10.1007/s10637-020-00970-x Publication Date: 2020-07-04T22:02:37Z
ABSTRACT
SummaryIbrutinib 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.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (45)
CITATIONS (15)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....