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
AUTHORS (10)
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.
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CITATIONS (15)
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