PT  - JOURNAL ARTICLE
AU  - Jens Teichert
AU  - Reinhard Sohr
AU  - Lothar Hennig
AU  - Frank Baumann
AU  - Konrad Schoppmeyer
AU  - Ulrich Patzak
AU  - Rainer Preiss
TI  - Identification and Quantitation of the <em>N</em>-Acetyl-L-cysteine <em>S</em>-Conjugates of Bendamustine and Its Sulfoxides in Human Bile after Administration of Bendamustine Hydrochloride
AID  - 10.1124/dmd.108.022855
DP  - 2009 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 292--301
VI  - 37
IP  - 2
4099  - http://dmd.aspetjournals.org/content/37/2/292.short
4100  - http://dmd.aspetjournals.org/content/37/2/292.full
SO  - Drug Metab Dispos2009 Feb 01; 37
AB  - We recently reported the detection of mercapturic acid pathway metabolites of bendamustine, namely, cysteine S-conjugates in human bile, which are supposed to subsequently undergo further metabolism. In this study, we describe the identification and quantitation of consecutive bendamustine metabolites occurring in human bile using authentic reference standards and the synthesis and structural confirmation of these compounds. Mass spectrometry data along with high-performance liquid chromatography retention data (fluorescence detection) of the synthetic reference standards were consistent with those of the metabolites found in human bile after administration of bendamustine hydrochloride to cancer patients. Analysis of the purified synthetic reference compounds showed a purity of at least 95%. Structural confirmation was achieved by one- and two-dimensional proton as well as carbon-13 NMR spectroscopy and mass spectrometry. A total of 16 bendamustine-related compounds were detected in the bile of patients, 11 of them were recovered as conjugates. Eight conjugates have been structurally confirmed as novel mercapturic acids and sulfoxides. Biliary excretion of the sulfoxides was twice that of the mercapturate precursors. Glutathione S-conjugates of bendamustine have not been detected in bile samples, indicating rapid enzymatic cleavage in humans. Both the lack of glutathione (GSH) conjugates and occurrence of diastereomeric sulfoxides emphasize species-related differences in the GSH conjugation of bendamustine between humans and rats. The total amount recovered in the bile as the sum of all conjugates over the period of 24 h after dosing averaged 5.2% of the administered dose. The question of whether the novel metabolites contribute to urinary excretion should be a target of future investigations. The American Society for Pharmacology and Experimental Therapeutics