Biased estimates of nonrenal clearance

The goal of the investigation was to critically evaluate published values for oral nonrenal clearance and their postulated dependence on renal function with drugs administered orally to subjects with varying renal function. Derivation of the pertinent equations indicated that the values reported for oral nonrenal clearance tend to systematically overestimate both the true oral and intravenous nonrenal clearances of these drugs. Computations were performed to confirm these findings not only for subjects with normal renal function, but also for patients with renal impairment. The computations evaluated the relevance of bioavailability and renal clearance of a drug for the bias in the estimates of true oral or intravenous nonrenal clearance. The results of the computations showed that the estimates for true oral and intravenous nonrenal clearance derived from oral data exceed systematically the true values in subjects with normal or reduced renal function. Also, a renal function dependent decrease of the true oral or intravenous nonrenal clearance is falsely diagnosed if apparent oral nonrenal clearance values are used for the estimates. The magnitude of bioavailability and renal clearance impact the bias in the estimates derived from oral data. For drugs with predominant renal excretion and small bioavailability the bias is largest. For drugs with predominant nonrenal elimination and large bioavailability the bias is smallest.