PT  - JOURNAL ARTICLE
AU  - Jens Teichert
AU  - Reinhard Sohr
AU  - Frank Baumann
AU  - Lothar Hennig
AU  - Karlheinz Merkle
AU  - Karel Caca
AU  - Rainer Preiss
TI  - 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
AID  - 10.1124/dmd.105.003624
DP  - 2005 Jul 01
TA  - Drug Metabolism and Disposition
PG  - 984--992
VI  - 33
IP  - 7
4099  - http://dmd.aspetjournals.org/content/33/7/984.short
4100  - http://dmd.aspetjournals.org/content/33/7/984.full
SO  - Drug Metab Dispos2005 Jul 01; 33
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics