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- benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione, CAS 171335-80-1, exatecan) in rats and humans were identified. Rats were dosed with the drug, and two major metabolites (UM-1 and UM-2) in the urine were isolated and purified by using ion-exchange column and HPLC. From NMR and mass spectra, they are suggested to be 4-hydroxymethyl metabolite (UM-1) and 3-hydroxy metabolite (UM-2) of the drug. Their chemical structures were confirmed by comparing their NMR spectra with those of chemically synthesized metabolites. Two major metabolites were found in human urine obtained in phase I trial. They were also confirmed to be UM-1 and UM-2 by LC/MS/MS by comparing their mass fragment patterns with those of synthetic metabolites.
Atsumi
R
R
Drug Metabolism and Analytical Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan. atsump4t@daiichipharm.co.jp
Oguma
T
T
Yoshioka
N
N
Konno
T
T
Okazaki
O
O
Fujimaki
Y
Y
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000652:urine*; D001711:Biotransformation; D002166:Camptothecin / Q000652:urine*; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley
D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin