Extrahepatic metabolism of ibrutinib.

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.

• Authors: Johannes J M Rood, Amer Jamalpoor, Stephanie van Hoppe, Matthijs J van Haren, Roeland E Wasmann, Manoe J Janssen, Alfred H Schinkel, Rosalinde Masereeuw, Jos H Beijnen, Rolf W Sparidans
• Journal: Investigational new drugs (Invest New Drugs) Vol. 39 Issue 1 Pg. 1-14 (02 2021) ISSN: 1573-0646 [Electronic] United States
• PMID: 32623551 (Publication Type: Journal Article)

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Antineoplastic Agents
• Multidrug Resistance-Associated Proteins
• Neoplasm Proteins
• Piperidines
• ibrutinib
• Cytochrome P-450 CYP3A
• Glutathione
• Adenine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors)
• ATP Binding Cassette Transporter, Subfamily G, Member 2 (antagonists & inhibitors)
• Acute Kidney Injury (chemically induced)
• Adenine (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
• Aged
• Animals
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, pharmacology)
• Cell Survival (drug effects)
• Cells, Cultured
• Cytochrome P-450 CYP3A (metabolism)
• Glutathione (metabolism)
• Humans
• Kidney Tubules, Proximal (drug effects)
• Male
• Mice
• Mice, Knockout
• Multidrug Resistance-Associated Proteins (antagonists & inhibitors)
• Neoplasm Proteins (antagonists & inhibitors)
• Piperidines (administration & dosage, adverse effects, pharmacokinetics)