Pharmacokinetic Modeling and Surgical Alteration of the Dog Urinary Tract in Relation to Aromatic Amine Bladder Carcincogenesis

摘要

Estimation of urinary levels of N-hydroxyarylamines, which are believed to be ultimate carcinogens for the bladder epithelium, has been complicated by the rapid resorption of these metabolites across the bladder wall and by their formation in the urine upon hydrolysis of N-hydroxyarylamine N-glucuronide conjugates. Therefore, a three-compartment pharmacokinetic model was developed with an analog-digital hybrid computer to separate absorption, metabolism, and distribution in the whole animal from events in the bladder lumen (deposition, hydrolysis and resorption). The total bladder exposure to the carcinogen, N-hydroxy-2-naphthylamine, was then simulated from experimental data; and urine pH and voiding intervals, both of which differ widely among species, were tested as variables. For humans and dogs, urine pH was found to be considerably more acidic than monkeys or rats; while voiding intervals in rats were considerably shorter than in monkeys, dogs or humans. The relative species susceptibilities, indicated by the model as total bladder exposure to the N-hydroxyarylamine metabolite under conditions of normal urine pH and frequency of micturition for each species, were in the order: human>dog>monkey>rat.