Slatter J G, Davis M R, Han D H, Pearson P G, Baillie T A
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Chem Res Toxicol. 1993 May-Jun;6(3):335-40. doi: 10.1021/tx00033a013.
Following administration to rats of a single ip dose (6.6 mg kg-1) of the investigational antitumor agent caracemide (N-acetyl-N,O-bis[methylcarbamoyl]hydroxylamine), the mercapturic acid derivative N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC) was identified in urine by thermospray LC-MS. Quantification of this conjugate was carried out by stable isotope dilution thermospray LC-MS, which indicated that the fraction of the caracemide dose recovered as AMCC in 24-h urine collections was 54.0 +/- 5.5% (n = 4). Since AMCC is known to represent a major urinary metabolite of methyl isocyanate (MIC) in the rat, the results of this study support the contention that caracemide yields MIC as a toxic intermediate in vivo. Furthermore, with the aid of a specifically deuterium-labeled analog of caracemide ([carbamoyloxy-C2H3]caracemide), it was shown that the methylcarbamoyl group of AMCC derived from both the O-methylcarbamoyl (72%) and N-methylcarbamoyl (28%) side chains of the drug. In view of these findings, it is concluded that caracemide acts as a latent form of MIC in vivo and that this reactive isocyanate (or labile S-linked conjugates thereof) may contribute to the antitumor properties and/or adverse side-effects of caracemide.
给大鼠单次腹腔注射剂量为6.6 mg kg-1的抗肿瘤药物卡拉西胺（N-乙酰基-N,O-双[甲基氨基甲酰基]羟胺）后，通过热喷雾液相色谱-质谱联用技术在尿液中鉴定出了硫醚氨酸衍生物N-乙酰基-S-(N-甲基氨基甲酰基)半胱氨酸（AMCC）。采用稳定同位素稀释热喷雾液相色谱-质谱联用技术对该缀合物进行定量分析，结果表明，在24小时尿液收集物中，以AMCC形式回收的卡拉西胺剂量分数为54.0 +/- 5.5%（n = 4）。由于已知AMCC是大鼠体内甲基异氰酸酯（MIC）的主要尿液代谢物，本研究结果支持了卡拉西胺在体内产生MIC作为毒性中间体的观点。此外，借助卡拉西胺的一种特异性氘标记类似物（[氨基甲酰氧基-C2H3]卡拉西胺），研究表明AMCC的甲基氨基甲酰基来源于药物的O-甲基氨基甲酰基（72%）和N-甲基氨基甲酰基（28%）侧链。鉴于这些发现，得出结论：卡拉西胺在体内作为MIC的潜在形式起作用，这种活性异氰酸酯（或其不稳定的S-连接缀合物）可能有助于卡拉西胺的抗肿瘤特性和/或不良副作用。
