title: Metabolism and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor apatinib in humans.
abstract: Apatinib is a new oral antiangiogenic molecule that inhibits vascular endothelial growth factor receptor-2. The present study aimed to determine the metabolism, pharmacokinetics, and excretion of apatinib in humans and to identify the enzymes responsible for its metabolism. The primary routes of apatinib biotransformation included E- and Z-cyclopentyl-3-hydroxylation, N-dealkylation, pyridyl-25-N-oxidation, 16-hydroxylation, dioxygenation, and O-glucuronidation after 3-hydroxylation. Nine major metabolites were confirmed by comparison with reference standards. The total recovery of the administered dose was 76.8% within 96 hours postdose, with 69.8 and 7.02% of the administered dose excreted in feces and urine, respectively. About 59.0% of the administered dose was excreted unchanged via feces. Unchanged apatinib was detected in negligible quantities in urine, indicating that systemically available apatinib was extensively metabolized. The major circulating metabolite was the pharmacologically inactive E-3-hydroxy-apatinib-O-glucuronide (M9-2), the steady-state exposure of which was 125% that of the apatinib. The steady-state exposures of E-3-hydroxy-apatinib (M1-1), Z-3-hydroxy-apatinib (M1-2), and apatinib-25-N-oxide (M1-6) were 56, 22, and 32% of parent drug exposure, respectively. Calculated as pharmacological activity index values, the contribution of M1-1 to the pharmacology of the drug was 5.42 to 19.3% that of the parent drug. The contribution of M1-2 and M1-6 to the pharmacology of the drug was less than 1%. Therefore, apatinib was a major contributor to the overall pharmacological activity in humans. Apatinib was metabolized primarily by CYP3A4/5 and, to a lesser extent, by CYP2D6, CYP2C9, and CYP2E1. UGT2B7 was the main enzyme responsible for M9-2 formation. Both UGT1A4 and UGT2B7 were responsible for Z-3-hydroxy-apatinib-O-glucuronide (M9-1) formation.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Juefang
authors.initials: J
authors.lastname: Ding
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Gao
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Dai
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Cen
authors.initials: C
authors.lastname: Xie
authors.forename: Haoyuan
authors.initials: H
authors.lastname: Jiang
authors.forename: Lijia
authors.initials: L
authors.lastname: Zhang
authors.forename: Dafang
authors.initials: D
authors.lastname: Zhong
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D011725:Pyridines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D011725:Pyridines; C553458:apatinib; D040301:Vascular Endothelial Growth Factor Receptor-2