Metabolic profile of [(14)C]bendamustine in rat urine and bile: preliminary structural identification of metabolites.
Bendamustine, a bifunctional alkylating agent, is currently in clinical trials for the treatment of hematological and other malignancies. Although it has been used in the former East Germany for more than 30 years, very limited information is available on its biotransformation. The objective of this investigation was to obtain information on the structures of metabolites excreted into rat urine and bile to understand the metabolic fate of bendamustine in vivo. Metabolites of [(14)C]bendamustine hydrochloride in rat urine and bile were determined using liquid chromatography-mass spectrometry (MS) in parallel with on-line radioactivity detection in samples obtained after i.v. dosing of 3 mg/kg. A total of 17 radioactive peaks were identified in rat urine and 10 in rat bile (2 were unique to bile). Four of these metabolites had been previously reported, whereas 15 are novel. Proposed structures of all metabolites detected are based on MS(n) spectra generated from a linear ion trap mass spectrometer. These results suggest that the major metabolic pathways in rat are oxidative and/or hydrolytic dehalogenation, oxidation, carboxylic acid formation, N-dealkylation, sulfation, and glutathione and cysteine (probably via glutathione) conjugation. The cysteine-conjugated compounds are observed in their N-acetylated cysteine (mercapturic acid) forms.
Chovan
James P
JP
Worldwide Drug Development, Drug Safety and Disposition, Cephalon, Inc., West Chester, PA, USA. jchovan@cephalon.com
Li
Feng
F
Yu
Erya
E
Ring
Steven C
SC
D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000652:urine; D000069461:Bendamustine Hydrochloride; D001646:Bile / Q000378:metabolism; D003640:Dealkylation; D005978:Glutathione / Q000378:metabolism; D008297:Male; D009588:Nitrogen Mustard Compounds / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D000069461:Bendamustine Hydrochloride; D005978:Glutathione; D000111:Acetylcysteine