QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.105.003624v1 33/7/984    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Teichert, J. Articles by Preiss, R. Search for Related Content PubMed PubMed Citation Articles by Teichert, J. Articles by Preiss, R.

SYNTHESIS AND CHARACTERIZATION OF SOME NEW PHASE II METABOLITES OF THE ALKYLATOR BENDAMUSTINE AND THEIR IDENTIFICATION IN HUMAN BILE, URINE, AND PLASMA FROM PATIENTS WITH CHOLANGIOCARCINOMA

Institute of Clinical Pharmacology (J.T., F.B., R.P.), Institute of Organic Chemistry (L.H.), and Department of Internal Medicine II (K.C.), University of Leipzig, Leipzig, Germany; Institute of Pharmacology and Toxicology (R.S.), Charité-University Medicine, Berlin, Germany; and Ribosepharm GmbH (K.M.), Munich, Germany

The alkylating agent bendamustine is currently in phase III clinical trials for the treatment of hematological malignancies and breast, lung, and gastrointestinal tumors. Renal elimination mainly as the parent compound is thought to be the primary route of excretion. Because polar biliary conjugates were expected metabolites of bendamustine, three cysteine S-conjugates were synthesized, purified by quantitative high-performance liquid chromatography (HPLC), and characterized by NMR spectroscopy and mass spectrometry (MS). HPLC assays with MS, as well as fluorescence detection of bile, urine, and plasma after single-dose intravenous infusion of 140 mg/m² bendamustine in five subjects with cholangiocarcinoma, indicated the existence of these phase II metabolites, which were identified as cysteine S-conjugates by comparison with the previously characterized synthetic reference standards. The sum of the three cysteine S-conjugates of bendamustine was determined in human bile and urine to be 95.8 and 26.0%, respectively, expressed as mean percentage of the sum of the parent compound and identified metabolites. The percentage of administered dose recovered in urine as cysteine S-conjugates ranged from 0.9 to 4.1%, whereas the total percentage of the administered dose excreted in urine as the parent drug and seven metabolites ranged from 3.8 to 16.3%. The identification of cysteine S-conjugates provide evidence that a major route of bendamustine metabolism in humans involves conjugation with glutathione. Results indicate the importance of phase II conjugation in the elimination of bendamustine, besides phase I metabolism and hydrolytic degradation, and require further investigation.

This article has been cited by other articles:

				B. D. Cheson and M. J. Rummel Bendamustine: Rebirth of an Old Drug J. Clin. Oncol., March 20, 2009; 27(9): 1492 - 1501. [Abstract] [Full Text] [PDF]

				J. Teichert, R. Sohr, L. Hennig, F. Baumann, K. Schoppmeyer, U. Patzak, and R. Preiss Identification and Quantitation of the N-Acetyl-L-cysteine S-Conjugates of Bendamustine and Its Sulfoxides in Human Bile after Administration of Bendamustine Hydrochloride Drug Metab. Dispos., February 1, 2009; 37(2): 292 - 301. [Abstract] [Full Text] [PDF]

				J. P. Chovan, F. Li, E. Yu, and S. C. Ring Metabolic Profile of [14C]Bendamustine in Rat Urine and Bile: Preliminary Structural Identification of Metabolites Drug Metab. Dispos., October 1, 2007; 35(10): 1744 - 1753. [Abstract] [Full Text] [PDF]