Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Drug Metab Dispos. 2012 Jul;40(7):1297-307. doi: 10.1124/dmd.112.045229. Epub 2012 Apr 4.
Bendamustine is an alkylating agent consisting of a mechlorethamine derivative, a benzimidazole group, and a butyric acid substituent. A human mass balance study showed that bendamustine is extensively metabolized and subsequently excreted in urine. However, limited information is available on the metabolite profile of bendamustine in human urine. The objective of this study was to elucidate the metabolic pathways of bendamustine in humans by identification of its metabolites excreted in urine. Human urine samples were collected up to 168 h after an intravenous infusion of 120 mg/m(2) (80-95 μCi) [(14)C]bendamustine. Metabolites of [(14)C]bendamustine were identified using liquid chromatography (high-resolution)-tandem mass spectrometry with off-line radioactivity detection. Bendamustine and a total of 25 bendamustine-related compounds were detected. Observed metabolic conversions at the benzimidazole and butyric acid moiety were N-demethylation and γ-hydroxylation. In addition, various other combinations of these conversions with modifications at the mechlorethamine moiety were observed, including hydrolysis (the primary metabolic pathway), cysteine conjugation, and subsequent biotransformation to mercapturic acid and thiol derivatives, N-dealkylation, oxidation, and conjugation with phosphate, creatinine, and uric acid. Bendamustine-derived products containing phosphate, creatinine, and uric acid conjugates were also detected in control urine incubated with bendamustine. Metabolites that were excreted up to 168 h after the infusion included products of dihydrolysis and cysteine conjugation of bendamustine and γ-hydroxybendamustine. The range of metabolic reactions is generally consistent with those reported for rat urine and bile, suggesting that the overall processes involved in metabolic elimination are qualitatively the same in rats and humans.
苯达莫司汀是一种烷化剂，由一个氯乙基亚硝脲衍生的、苯并咪唑基团和丁酸取代基组成。一项人体物质平衡研究表明，苯达莫司汀广泛代谢，随后以尿液形式排泄。然而，关于人尿中苯达莫司汀代谢产物的信息有限。本研究旨在通过鉴定人尿中苯达莫司汀的代谢产物来阐明其在人体内的代谢途径。在静脉输注 120mg/m²（80-95μCi）[¹⁴C]苯达莫司汀后 168 小时内收集人尿样。使用带有离线放射性检测的液相色谱（高分辨率）-串联质谱法鉴定[¹⁴C]苯达莫司汀的代谢产物。检测到苯达莫司汀和总共 25 种苯达莫司汀相关化合物。在苯并咪唑和丁酸部分观察到的代谢转化为 N-去甲基化和γ-羟化。此外，还观察到在氯乙基亚硝脲部分的这些转化与修饰的各种其他组合，包括水解（主要代谢途径）、半胱氨酸结合，随后生物转化为巯基尿酸和硫醇衍生物、N-脱烷基化、氧化和与磷酸盐、肌酸和尿酸的结合。在用苯达莫司汀孵育的对照尿中也检测到含有磷酸盐、肌酸和尿酸结合物的苯达莫司汀衍生产物。输注后 168 小时内排泄的代谢产物包括苯达莫司汀和γ-羟苯达莫司汀的双水解和半胱氨酸结合产物。代谢反应的范围通常与大鼠尿和胆汁中的报道一致，这表明在大鼠和人中，代谢消除所涉及的整体过程在质上是相同的。
