In vitro metabolism of the novel, highly selective oral angiogenesis inhibitor motesanib diphosphate in preclinical species and in humans.
Motesanib diphosphate is a novel, investigational, highly selective oral inhibitor of the receptor tyrosine kinases vascular endothelial growth factor receptors 1, 2, and 3, the platelet-derived growth factor receptor, and the stem cell factor receptor (Kit). The in vitro metabolic profiles of [(14)C]motesanib were examined by using microsomes and hepatocytes from preclinical species and humans. Several oxidative metabolites were observed and characterized by tandem mass spectrometry, nuclear magnetic resonance spectroscopy, and coinjection with authentic standards. Cytochrome P450 (P450) 3A4 is the major isozyme involved in the oxidative biotransformation of motesanib, but the CYP2D6 and CYP1A isozymes also make minor contributions. In hepatocyte incubations, oxidative and conjugative pathways were observed for all species examined, and indoline N-glucuronidation was the dominant pathway. Three less common and novel phase II conjugates of the indoline nitrogen were detected in hepatocytes and in microsomes supplemented with specific cofactors, including N-carbamoyl glucuronide, N-glucose, and N-linked beta-N-acetylglucosamine. An N-glucuronide metabolite was the most frequently observed phase II conjugate in liver microsomes of all species, whereas the N-acetylglucosamine conjugate was observed only in monkey liver microsomes. Incubations with recombinant human UDP-glucuronosyltransferases (UGTs) and inhibition by the UGT1A4 and UGT1A1 substrates/inhibitors imipramine and bilirubin suggested that UGT1A4 is the major UGT isozyme catalyzing the N-glucuronidation of motesanib, with a minor contribution from UGT1A1. The in vitro metabolic profiles were similar between the human and preclinical species examined. All metabolites found in humans were also detected in other species.
Li
Chun
C
Department of Pharmacokinetics and Drug Metabolism, Mail Stop 30E-2-B, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320-1799, USA.
Kuchimanchi
Mita
M
Hickman
Dean
D
Poppe
Leszek
L
Hayashi
Mike
M
Zhou
Yihong
Y
Subramanian
Raju
R
Kumar
Gondi
G
Surapaneni
Sekhar
S
D000284:Administration, Oral; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D007211:Indoles / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D053858:Metabolic Networks and Pathways; D055442:Metabolome / Q000187:drug effects; D008862:Microsomes, Liver / Q000378:metabolism*; D000099148:UGT1A1 Enzyme
D003577:Cytochrome P-450 Enzyme System; D020719:Glucuronides; D014453:Glucuronosyltransferase; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000099148:UGT1A1 Enzyme; C057812:indoline