noted that the parameter values reported by Kearns and Wilson were derived from a one-dog study.
No literature information regarding the pharmacokinetics of I in nephrectomized dogs is available. In this study, serum concentrations of I in nephrectomized dogs were lower than the corresponding concentrations in the normal ones. This observation suggests a greater volume of distribution for the nephrectomized dogs, which could be attributable to a reduced protein binding of I in the nephrectomized state. Reduced binding of highly bound organic acid to uremic plasma protein has been demonstrated for phenytoin, resulting in an increased volume of distribution (18). A similar mechanism may be suggested for 1, which is also an organic acid with extensive protein binding (9). The reduction in binding of 1 to serum protein on nephrectomy is shown in Table IV for two dogs, one normal and the other nephrectornized. The protein binding was independent of concentration in the range of 5-20 pg/mL. The percentage of I unbound to serum protein in the nephrectornized dog, 6.8 f 1 .O%, was significantly greater than that in the normal dog, 1.3 f 0.3% (p < 0.001). In a separate binding study of I in uremic patients (19), the fraction of free I in uremic plasma was also found to be higher than that in normal plasma (Table IV). The dogs used for this investigation were nephrectomized 3 d prior to the study and presumably were approaching the chronic uremic state.
Nephrectomy did not significantly alter the half-life of 1 in dogs; however, increases in both the volume of distribution and total clearance were apparent.
Sincc <8W of the dose is excreted intact in the urine (9.20). the lack of effect of nephrectomy on thc half-life of I was anticipated. Nephrectomy induced increases in the total clearance and volume of distribution. The increased volume of distribution could result from a decreased protein binding of I in the nephrectomized state (Table IV), leaving more free drug available for distribution into the body tissue. The increase in total clearance is secondary to the increase in volume of distribution.
The effects of renal failure on the disposition of I in dogs and those of benoxaprofen in humans (16) are disparate. In dogs, the half-life of I remained unchanged, whereas the volume of distribution and total clearance increased. In humans the half-life of benoxaprofen was significantly prolonged with no distinct changes in other pharmacokinetic parameters. The disparity cautions against the extrapolation of conclusions from one drug analogue to another and from animal model to human subject.