Urinary metabolites of DX-8951, a novel camptothecin analog, in rats and humans

Urinary metabolites of DX-8951 ((1S,9S)1-amino-9-ethyl-5-fluoro-1,2,3,9, 12 ,15-hexahydro-9 -hydroxy-4-methyl-10H,13H-benzolde] pyrano [3',4':6,7] indo lizino[1,2-b] quinoline-10, 13-dione, CAS 171335-80-1, exatecan) in rats an d humans were identified. Rats were dosed with the drug, and two major meta bolites (UM-1 and UM-2) in the urine were isolated and purified by using io n-exchange column and HPLC. From NMR and mass spectra, they are suggested t o be 4-hydroxymethyl metabolite (UM-1) and 3-hydroxy metabolite (UM-2) of t he drug. Their chemical structures were confirmed by comparing their NMR sp ectra with those of chemically synthesized metabolites. Two major metabolit es were found in human urine obtained in phase I trial. They were also conf irmed to be UM-1 and UM-2 by LC/MS/MS by comparing their mass fragment patt erns with those of synthetic metabolites.