Characterization of Enzymes Involved in Nintedanib Metabolism in HumansS

Nintedanib, which is used to treat idiopathic pulmonary fibrosis and non-small cell lung cancer, is metabolized to a pharmacologi-cally inactive carboxylate derivative, BIBF1202, via hydrolysis and subsequently by glucuronidation to BIBF1202 acyl-glucuronide (BIBF1202-G). Since BIBF1202-G contains an ester bond, it can hydrolytically cleaved to BIBF1202. In this study, we sought characterize these metabolic reactions in the human liver and testine. Nintedanib hydrolysis was detected in human liver micro-somes (HLMs) (Clearance [CLint]: 102.8 +/- 18.9 mL/min per protein) but not in small intestinal preparations. CES1 was sug-gested to be responsible for nintedanib hydrolysis according to periments using recombinant hydrolases and hydrolase inhibitors well as proteomic correlation analysis using 25 individual HLM. BIBF1202 glucuronidation in HLM (3.6 +/- 0.3 mL/min per mg protein) was higher than that in human intestinal microsomes (1.5 +/- 0.06 mL/min per mg protein). UGT1A1 and gastrointestinal UGT1A7, UGT1A8, and UGT1A10 were able to mediate BIBF1202 glucuronidation. The impact of UGT1A1 on glucuronidation was supported by the finding that liver microsomes from subjects homozygous for the UGT1A1*28 allele showed significantly lower activity than those from subjects carrying the wild-type UGT1A1 allele. Interestingly, BIBF1202-G was converted to BIBF1202 in HLS9 at 70-fold higher rates than the rates of BIBF1202 glucuronidation. An inhibition study and proteomic correlation analy- sis suggested that b-glucuronidase is responsible for hepatic BIBF1202-G deglucuronidation. In conclusion, the major metabolic re- actions of nintedanib in the human liver and intestine were quantita- tively and thoroughly elucidated. This information could be helpful to understand the inter- and intraindividual variability in the efficacy of nintedanib.