In vitro hepatic metabolism of cediranib, a potent vascular endothelial growth factor tyrosine kinase inhibitor: interspecies comparison and human enzymology.
The in vitro metabolism of cediranib (4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) of all three VEGF receptors in late-stage development for the treatment of colorectal cancer and recurrent glioblastoma was investigated in hepatic proteins from preclinical species and humans using radiolabeled material. In human hepatocyte cultures, oxidative and conjugative metabolic pathways were identified, with pyrrolidine N(+)-glucuronidation being the major route. The primary oxidative pathways were di-and trioxidations and pyrrolidine N-oxidation. All metabolites with the exception of the N(+)-glucuronide metabolite were observed in rat and cynomolgus monkey hepatocyte preparations. Additional metabolism studies in liver microsomes from these or other preclinical species (CD-1 mouse, Han Wistar rat, Dunkin Hartley guinea pig, Göttingen mini-pig, New Zealand White rabbit, beagle dog, and cynomolgus and rhesus monkey) indicated that the N(+)-glucuronide metabolite was not formed in these additional species. Incubations with recombinant flavin-containing monooxygenase (FMO) and UDP-glucuronosyltransferase (UGT) enzymes and inhibition studies using the nonselective cytochrome P450 (P450) chemical inhibitor 1-aminobenzotriazole in human hepatocytes indicated that FMO1 and FMO3 contributed to cediranib N-oxidation, whereas UGT1A4 had a major role in cediranib N(+)-glucuronidation. P450 enzymes had only a minor role in the metabolism of cediranib. In conclusion, species differences in the formation of the N(+)-glucuronide metabolite of cediranib were observed. All other metabolites of cediranib found in humans were also detected in rat and cynomolgus monkey. Non-P450 enzymes are predominantly involved in the metabolism of cediranib, and this suggests that clinical drug interactions involving other coadministered drugs are unlikely.
Schulz-Utermoehl
Timothy
T
Clinical Pharmacologyand DMPK Department-Alderley Park, AstraZeneca UK Ltd., Macclesfield, Cheshire, UK. timothy.schulz-utermoehl@astrazeneca.com
Spear
Michael
M
Pollard
Christopher R J
CR
Pattison
Christine
C
Rollison
Helen
H
Sarda
Sunil
S
Ward
Michelle
M
Bushby
Nick
N
Jordan
Angela
A
Harrison
Mike
M
D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D006168:Guinea Pigs; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000378:metabolism*; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D050216:Metabolic Detoxication, Phase I; D050217:Metabolic Detoxication, Phase II; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D010105:Oxygenases / Q000378:metabolism; D011799:Quinazolines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013045:Species Specificity; D013552:Swine; D013556:Swine, Miniature; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D007211:Indoles
D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D010105:Oxygenases; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases; D042461:Vascular Endothelial Growth Factor A; C020066:dimethylaniline monooxygenase (N-oxide forming); C500926:cediranib; D007211:Indoles