title: Stabilities of neutral and basic esters of bendamustine in plasma compared to the parent compound: kinetic investigations by HPLC.
abstract: Esters of the cytostatic bendamustine (1), previously demonstrated to be much more potent than the parent compound as antiproliferative agents in vitro, were investigated for stability in buffer and plasma, as well as against porcine liver esterase in the presence of different amounts of albumin using a validated RP-HPLC method with fluorescence detection. The hydrolysis of the nitrogen mustard moiety was retarded (for 1: approximately 130 vs. 11 min) in the presence of plasma proteins. For the derivatives, both cleavage of ester and nitrogen mustard moieties were analyzed. Enzymatic hydrolysis was very fast in the case of 2-pyrrolidino-, 2-piperidino- and 2-(4-methylpiperazino)-ethyl esters, whereas methyl, ethyl, morpholinoethyl and branched 2-pyrrolidinoethyl esters were considerably more stable (half-lives between 41 and 116 min, compared to <5 min). Inhibition by physostigmine indicated unspecific cholinesterases to be involved in the rapid ester cleavage. Due to lower protein content and higher enzymatic activity in murine compared to human plasma, reduced stability of all investigated esters in mouse plasma (t½<2 min) has to be taken into account with respect to the design of animal studies.
authors.affiliation: Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Huber
authors.affiliation: Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Antoni
authors.affiliation: Welserstr 3, D-91207 Lauf an der Pegnitz, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schickaneder
authors.affiliation: Wiesenstraße 16, D-90542 Eckental, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Schickaneder
authors.affiliation: Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Bernhardt
authors.affiliation: Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany. Electronic address: armin.buschauer@chemie.uni-regensburg.de.
authors.forename: A
authors.initials: A
authors.lastname: Buschauer
mesh_terms: D000818:Animals; D000069461:Bendamustine Hydrochloride; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004952:Esters / Q000097:blood; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009588:Nitrogen Mustard Compounds / Q000097:blood*; D010599:Pharmacokinetics
chemical_list: D004952:Esters; D009588:Nitrogen Mustard Compounds; D000069461:Bendamustine Hydrochloride
keywords: Bendamustine ester; Butyrylcholinesterase; Ester cleavage; Hydrolysis; Nitrogen mustard