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First published on April 21, 2005; DOI: 10.1124/dmd.105.003624

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Jens Teichert
Reinhard Sohr
Frank Baumann
Lothar Hennig
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Rainer Preiss
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Received for publication January 10, 2005.
Revised April 20, 2005.
Accepted for publication April 20, 2005.

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

Jens Teichert 1*, Reinhard Sohr 2, Frank Baumann 1, Lothar Hennig 1, Karlheinz Merkle 3, Karel Caca 4, Rainer Preiss 1

1 University of Leipzig 2 Charite, University Medicine Berlin 3 ribosepharm GmbH 4 University Hospital of Leipzig

* Address correspondence to: E-mail: jens.teichert{at}medizin.uni-leipzig.de

Abstract

Abstract 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 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 nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS). HPLC assays with MS as well as fluorescence detection of bile, urine, and plasma after single-dose intravenous infusion of bendamustine 140 mg/m2 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 determined in human bile and urine was 95.8 and 26.0 %, respectively, expressed as mean percentage of the sum of 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 administered dose excreted in urine as parent drug and seven metabolites ranged from 3.8 -16.3 %. The identification of cysteine S-conjugates provide evidence that a major route of bendamustine metabolism in humans involves conjugation with glutathione (GSH). Results indicate the importance of phase II conjugation in the elimination of bendamustine beside phase I metabolism and hydrolytic degradation and require further investigation.


Key words: anticancer agents, metabolite identification, phase II drug metabolism


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