title: Metabolism and urinary excretion of a new quinoline anticancer drug, TAS-103, in humans.
abstract: 1. TAS-103, a novel condensed quinoline derivative, has been developed as an anticancer drug targeting topoisomerases I and II. 2. The purpose of the present study was to characterize the metabolism and urinary excretion of TAS-103 after the intravenous infusion of a single dose to patients in Phase I clinical trials. 3. Five metabolites were detected using high-performance liquid chromatography (HPLC) photodiode array and a precursor scan by liquid chromatography mass spectrometry mass spectrometry (LC/MS/MS). 4. Structures of the five metabolites were determined using the results of enzymatic hydrolysis and the analysis of production mass spectra obtained by LC/MS/MS, and by comparing HPLC retention times and UV, mass and production mass spectra of authentic standards. 5. The metabolites were identified as demethyl-TAS-103 glucuronide (DM-TAS-103-G), TAS-103 glucuronide (TAS-103-G), TAS-103 glucuronide N-oxide (NO-TAS-103-G), demethyl-TAS-103 (DM-TAS-103) and TAS-103 N-oxide (NO-TAS-103). 6. The mean total amount of TAS-103 and TAS-103-G in urine was only 6.03% of the dose, suggesting that urine is not the main elimination route. TAS-103 was extensively metabolized, and a small percentage of the parent drug (0.41%) was found in urine.
authors.affiliation: Pharmacokinetics Research Laboratory, Taiho Pharmaceutical Co, Ltd, Tokushima, Japan. ryu-azuma@taiho.co.jp
authors.forename: R
authors.initials: R
authors.lastname: Azuma
authors.forename: M
authors.initials: M
authors.lastname: Saeki
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Hagiwara
authors.forename: L B
authors.initials: LB
authors.lastname: Grochow
authors.forename: R C
authors.initials: RC
authors.lastname: Donehower
mesh_terms: D000634:Aminoquinolines / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000652:urine*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000652:urine*; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D006801:Humans; D007192:Indenes / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000652:urine*; D007262:Infusions, Intravenous; D013058:Mass Spectrometry; D015394:Molecular Structure; D013056:Spectrophotometry, Ultraviolet; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D020719:Glucuronides; D007192:Indenes; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C106647:6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one