In modern pharmacokinetic analysis, the urinary bladder is usually viewed as a nonreturning compartment or storage site for renally excreted compounds. Our previous studies have indicated appreciable bladder resorption of drugs. The present study used computer simulations to evaluate the quantitative importance of several potential determinants of bladder resorption, namely the bladder resorption rate constant (k(a)), interval between bladder voiding (Delta t(void)), ratio of renal elimination rate constant to overall elimination rate constant (k(ex):k(el) ratio), and K-el or t(1/2). The data identified k(a), Delta t(void), and k(ex):k(el) ratio as the three most important determinants of the rate and extent of bladder resorption. We further examined the errors introduced in the derived pharmacokinetic parameters due to omission of bladder resorption. Plasma concentration-time profiles and urinary excretion-time profiles were generated by simulations using different values of k(a), Delta t(void), and k(ex):k(el) ratio. These profiles were used to derive the pharmacokinetic parameters, including the renal clearance (CL(renal)), total body clearance (CL(total)), nonrenal clearance (CL(nonrenal)), t(1/2), mean residence time (MRT), amount and fraction of dose excreted in urine (A(ex) and f(e)), and volume of distribution at steady state (Vd(ss)). Data show that resorption of drug from the bladder into the systemic circulation increased the area under the plama concentration-time profile, MRT and t(1/2) was dependent on k(a), k(ex):k(el) ratio, and Delta t(void). Underestimation in CL(renal), A(ex), and f(e) was not dependent on the k(ex):k(el) ratio, but was affected by changes in k(a) and Delta t(void). CL(renal) and f(e) were the most sensitive pharmacokinetic parameters, with a greater than or equal to 50% underestimation at a k(a) value that were reported previously, for the bladder absorption of antipyrine in rats with intact urothelium. In summary, these data indicate (i) alteration in the plasma concentration-time profiles and urinary excretion-time profiles due to bladder resorption, and (ii) substantial over- or underestimation in the derived in the derived pharmacokinetic parameters due to erroneous omission of bladder resorption.
