Urinary excretion: does it accurately reflect relative differences in bioavailability/systemic exposure when renal clearance is nonlinear?

PURPOSE: The purpose of this study was to assess the influence of nonlinear renal clearance on the ability of urinary excretion data to accurately determine relative differences in systemic exposure and bioavailability.
METHODS: Serum concentration and urinary excretion-time profiles were simulated assuming an open one-compartmental model with first-order absorption, linear nonrenal clearance, and either linear or nonlinear renal clearance (saturable secretion). Renal clearance comprised 5% or 95% of total clearance. Doses were varied over a 100-fold range (10-fold decrease/increase from the reference dose). Relative systemic exposures were based on the ratios of AUC and C(max) and the corresponding ratios of cumulative amount excreted in urine (A(e)) and the maximum urinary excretion rate. Relative bioavailability was based on the ratios of A(e) and the test to reference dose (D(ratio)).
RESULTS: When renal clearance was linear and urinary excretion data were used to assess relative systemic exposure and relative bioavailability, no significant errors in accuracy were observed. However, when renal clearance was nonlinear, errors in the accuracy of estimation of relative bioavailability (Clr =5% only) and relative systemic exposure ranged from -53% to +125%; minimal error in accuracy existed in the estimation of relative bioavailability when Clr = 95% (-3% to +6%).
CONCLUSIONS: Prior to the use of urinary excretion data to assess relative systemic exposure or bioavailability, the relationship between serum concentration and renal clearance should be established.