A Pharmacokinetic Model To Predict Exposure Of The Bladder Epithelium To Urinary N-Hydroxyarylamine Carcinogens As A Function Of Urine Ph, Voiding Interval, And Resorption

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 interval, 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 greater than or equal to dog greater than monkey greater than rat. This is consistent with the reported carcinogenic potency of 2-naphthylamine in these species and suggests that urine pH and voiding interval are important determinants in aromatic amine-induced bladder cancer.