Bonfanti M, Magagnotti C, Bonati M, Fanelli R, Airoldi L
Laboratory of Enviromental Pharmacology and Toxicology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Cancer Res. 1988 Jul 1;48(13):3666-9.
N-Nitrosodibutylamine and its omega-hydroxylated metabolite N-nitrosobutyl(4-hydroxybutyl)amine (NB4HBA) induce tumors in the urine bladder of different animal species through their common urinary metabolite N-nitrosobutyl(3-carboxypropyl)amine (NB3CPA), resulting from the oxidation of the alcoholic group of NB4HBA to a carboxylic group. NB4HBA disappearance from blood, the formation of its main metabolites, NB3CPA and NB4HBA-glucuronide (NB4HBA-G), and their urinary excretion, were investigated in rats after an i.v. dose of 1 mg/kg (5.7 mumol/kg). NB3CPA and NB4HBA-G formation was readily detectable 2 min after treatment and levels were still measurable at 120 and 30 min, respectively. The parent compound disappeared from blood 90 min after injection. The NB4HBA blood concentration-time profile was adequately described by a one-compartmental linear model. NB4HBA half-life was 8 min, total body clearance and renal clearance were 86.1 and 0.22 ml/min/kg, respectively. The 0-96-h urinary excretion of NB4HBA was 0.3% of the administered dose. NB3CPA half-life was 15 min; NB3CPA and NB4HBA-G urinary excretion were 36 and 11.7%, respectively, urinary excretion of known compounds accounting for less than 50%. After i.v. injection of NB3CPA equimolar to the NB4HBA dose, only 50% of unchanged compound was recovered in the urine and after NB4HBA-G, 41% of the administered dose was excreted unchanged, NB3CPA accounting for 10%. Thus NB3CPA and NB4HBA-G might undergo further biotransformation, suggesting that NB3CPA may not be the ultimate carcinogen responsible for urinary bladder tumor induction.
N-亚硝基二丁胺及其ω-羟基化代谢产物N-亚硝基丁基(4-羟基丁基)胺(NB4HBA)通过其共同的尿液代谢产物N-亚硝基丁基(3-羧丙基)胺(NB3CPA)在不同动物物种的膀胱中诱发肿瘤，NB3CPA是由NB4HBA的醇基氧化为羧基产生的。在大鼠静脉注射1mg/kg(5.7μmol/kg)剂量后，研究了NB4HBA从血液中的消失情况、其主要代谢产物NB3CPA和NB4HBA-葡萄糖醛酸苷(NB4HBA-G)的形成及其尿液排泄情况。治疗后2分钟即可轻易检测到NB3CPA和NB4HBA-G的形成，其水平在120分钟和30分钟时仍可测量。注射后90分钟母体化合物从血液中消失。NB4HBA的血药浓度-时间曲线可用单室线性模型充分描述。NB4HBA的半衰期为8分钟，全身清除率和肾清除率分别为86.1和0.22ml/min/kg。NB4HBA在0-96小时的尿液排泄量为给药剂量的0.3%。NB3CPA的半衰期为15分钟；NB3CPA和NB4HBA-G的尿液排泄率分别为36%和11.7%，已知化合物的尿液排泄率不到50%。静脉注射与NB4HBA剂量等摩尔的NB3CPA后，尿液中仅回收了50%的未变化化合物，注射NB4HBA-G后，给药剂量的41%以未变化形式排泄，其中NB3CPA占10%。因此，NB3CPA和NB4HBA-G可能会经历进一步的生物转化，这表明NB3CPA可能不是导致膀胱肿瘤诱发的最终致癌物。
