Pyrotinib is a novel irreversible EGFR/HER2 dual
tyrosine kinase inhibitor that is used to treat HER2-positive
breast cancer. In this study we investigated the metabolism and disposition of
pyrotinib in six healthy Chinese men after a single oral dose of 402 mg of [14C]
pyrotinib. At 240 h postdose, the mean cumulative excretion of the dose radioactivity was 92.6%, including 1.7% in urine and 90.9% in feces. In feces, oxidative metabolites were detected as major drug-related materials and the primary metabolic pathways were O-depicoline (M1), oxidation of
pyrrolidine (M5), and oxidation of
pyridine (M6-1, M6-2, M6-3, and M6-4). In plasma, the major circulating entities identified were
pyrotinib, SHR150980 (M1), SHR151468 (M2), and SHR151136 (M5), accounting for 10.9%, 1.9%, 1.0%, and 3.0%, respectively, of the total plasma radioactivity based on the AUC0-∞ ratios. Approximately 58.3% of the total plasma radioactivity AUC0-∞ was attributed to covalently bound materials. After incubation of human plasma with [14C]
pyrotinib at 37 °C for 2, 5, 8, and 24 h, the recovery of radioactivity by extraction was 97.4%, 91.8%, 69.6%, and 46.7%, respectively, revealing covalent binding occurred independently of
enzymes. A group of
pyrotinib adducts, including
pyrotinib-
lysine and
pyrotinib adducts of the
peptides Gly-Lys, Lys-
Ala, Gly-Lys-Ala, and Lys-Ala-Ser, was identified after HCl hydrolysis of the incubated plasma. Therefore, the
amino acid residue Lys190 of
human serum albumin was proposed to covalently bind to
pyrotinib via Michael addition. Finally, the covalently bound
pyrotinib could dissociate from the human
plasma protein and be metabolized by oxidation and excreted via feces.