title: Metabolite profiling of bendamustine in urine of cancer patients after administration of [14C]bendamustine.
abstract: Bendamustine is an alkylating agent consisting of a mechlorethamine derivative, a benzimidazole group, and a butyric acid substituent. A human mass balance study showed that bendamustine is extensively metabolized and subsequently excreted in urine. However, limited information is available on the metabolite profile of bendamustine in human urine. The objective of this study was to elucidate the metabolic pathways of bendamustine in humans by identification of its metabolites excreted in urine. Human urine samples were collected up to 168 h after an intravenous infusion of 120 mg/m(2) (80-95 μCi) [(14)C]bendamustine. Metabolites of [(14)C]bendamustine were identified using liquid chromatography (high-resolution)-tandem mass spectrometry with off-line radioactivity detection. Bendamustine and a total of 25 bendamustine-related compounds were detected. Observed metabolic conversions at the benzimidazole and butyric acid moiety were N-demethylation and γ-hydroxylation. In addition, various other combinations of these conversions with modifications at the mechlorethamine moiety were observed, including hydrolysis (the primary metabolic pathway), cysteine conjugation, and subsequent biotransformation to mercapturic acid and thiol derivatives, N-dealkylation, oxidation, and conjugation with phosphate, creatinine, and uric acid. Bendamustine-derived products containing phosphate, creatinine, and uric acid conjugates were also detected in control urine incubated with bendamustine. Metabolites that were excreted up to 168 h after the infusion included products of dihydrolysis and cysteine conjugation of bendamustine and γ-hydroxybendamustine. The range of metabolic reactions is generally consistent with those reported for rat urine and bile, suggesting that the overall processes involved in metabolic elimination are qualitatively the same in rats and humans.
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. anne-charlotte.dubbelman@slz.nl
authors.forename: Anne-Charlotte
authors.initials: AC
authors.lastname: Dubbelman
authors.forename: Robert S
authors.initials: RS
authors.lastname: Jansen
authors.forename: Hilde
authors.initials: H
authors.lastname: Rosing
authors.forename: Mona
authors.initials: M
authors.lastname: Darwish
authors.forename: Edward
authors.initials: E
authors.lastname: Hellriegel
authors.forename: Philmore
authors.initials: P
authors.lastname: Robertson
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000493:pharmacokinetics / Q000652:urine*; D000069461:Bendamustine Hydrochloride; D002250:Carbon Radioisotopes; D003404:Creatinine / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D003640:Dealkylation / Q000502:physiology; D006801:Humans; D006868:Hydrolysis; D006900:Hydroxylation; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D009369:Neoplasms / Q000652:urine*; D009588:Nitrogen Mustard Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000652:urine*; D010084:Oxidation-Reduction; D010710:Phosphates / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002250:Carbon Radioisotopes; D009588:Nitrogen Mustard Compounds; D010710:Phosphates; D014527:Uric Acid; D000069461:Bendamustine Hydrochloride; D003404:Creatinine; D003545:Cysteine