Original Article - Journal of Pharmaceutical Chemistry & Chemical Science (2018) Volume 0, Issue 0
Updates on bendamustine metabolites in plasma and excreta of sprague dawley rats and cynomolgus monkeys.
A derivative of bendamustine, designed for longer duration of activity and better distribution into tissues, was intravenously infused to rats and monkeys. The parent BM derivative was rapidly metabolized in both species. Consequently, BM and BM-related metabolites were essentially all that were detected and identified from plasma and excreta of both species. A variety of new metabolites have been identified, including 5 intact direct conjugates of glutathione, 2 cysteinyl-glycine conjugates, 1 glucuronic acid conjugate, and 1 taurine conjugate on the butyric acid side, in addition to a new metabolite of an aziridine partial structure formed due to N-dealkylation and intra-molecular nucleophilic/electrophilic reaction. The overall biotransformation pathways are similar to those previously reported, including substitution of the chlorine atoms (glutathione, cysteinyl-glycine, mercapturic acid, hydroxyl, creatinine, uric acid and phosphate), N-dealkylation to cleave the chloroethyl moiety, and γ-hydroxylation on the butyric acid moiety. However, new biotransformation pathways have been discovered in the current work, unrelated to the derivatization of the parent compound, which includes phase II conjugation on the butyric acid with glucuronic acid and taurine in rat, and a proposed intramolecular nucleophilic/electrophilic mechanism in monkey. No metabolite due to the previously reported N-demethylation was detected from either species in the current study. In addition, based on exact mass measurements of both survey full scan and dependent product ion data, an imine structure is presented instead of an aldehyde structure that was proposed previously, and another metabolite has been postulated to have a carboxylic acid functionality on the original chloroethyl moiety.Author(s): Li AC, Erya Yu, Ring SC, Chovan JP