Human variability in the renal elimination of foreign compounds and renal excretion-related uncertainty factors for risk assessment

Dorne, J.L., Walton, K. and Renwick, A.G. (2004) Human variability in the renal elimination of foreign compounds and renal excretion-related uncertainty factors for risk assessment. Food and Chemical Toxicology, 42 (2), 275-298. (doi:10.1016/j.fct.2003.09.002).

Abstract

Renal excretion is an important route of elimination for xenobiotics and three processes determine the renal clearance of a compound [glomerular filtration (about 120 ml/min), active renal tubular secretion (>120 ml/min) and passive reabsorption (<120 ml/min)]. Human variability in kinetics has been quantified using a database of 15 compounds excreted extensively by the kidney (>60% of a dose) to develop renal-excretion related uncertainty factors for the risk assessment of environmental contaminants handled via this route. Data were analysed from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups using parameters relating primarily to chronic exposure [renal and total clearances, area under the plasma concentration time-curve (AUC)] and acute exposure (Cmax). Interindividual variability in kinetics was low for both routes of exposure, with coefficients of variation of 21% (oral) and 24% (intravenous) that were largely independent of the renal processes involved. Renal-excretion related uncertainty factors were below the default kinetic uncertainty factor of 3.16 for most subgroups analysed with the exception of the elderly (oral data) and neonates (intravenous data) for whom renal excretion-related factors of 4.2 and 3.2 would be required to cover up to 99% of these subgroups respectively.
CLr Renal clearance CL Total clearance AUC Area under the plasma-concentration-time-curve Cmax Maximum plasma concentration Ns Number of studies Np Number of publications n number of subjects XW Arithmetic weighted mean (normal distribution) SDw Weighted standard deviation (normal distribution) CVN Coefficient of variation (normal distribution) GMW Geometric weighted mean (lognormal distribution) GSDw Weighted geometric standard deviation (lognormal distribution) CVLN Coefficient of variation (lognormal distribution) GF Glomerular filtration TS Tubular secretion

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