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Pharmacokinetic Profile and Metabolism of N-Nitrosobutyl-(4-hydroxybutyl)amine in Rats¹

Laboratory of Environmental Pharmacology and Toxicology [Mar. B., C. M., R. F., L. A.] and Laboratory of Clinical Pharmacology [Mau. B.], Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Eritrea 62, 20157 Milan, Italy

N-Nitrosodibutylamine and its -hydroxylated metabolite N-nitrosobutyl(4-hydroxybutyl)amine (NB4HBA) induce tumors in the urinary 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 µmol/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.

¹ This work was supported by the Italian National Research Council, Special Project ‘Oncology,’ Contract 86.02607.44.

² To whom requests for reprints should be addressed.

Received 10/ 1/87. Revised 2/17/88. Accepted 2/25/88.

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