Estimating renal and hepatic clearance rates of organophosphate esters in humans: Impacts of intrinsic metabolism and binding affinity with plasma proteins

Abstract

The renal and hepatic clearance rates of organophosphate esters (OPEs) in humans were estimated. Six OPEs and their corresponding diester metabolites (mOPEs) were quantified respectively in 30 paired human plasma and urine samples collected in Hengshui, Hebei province, China. The renal clearance rate (CLrenal) of triphenyl phosphate (TPHP), tris(chloroethyl) phosphate (TCEP) and tris(1,3-dichloro-isopropyl) phosphate (TDCIPP) was estimated to be 68.9, 50.9 and 33.3 mL/kg/day, respectively, while it was not calculated for other three OPEs due to the low detection frequencies in human samples. To estimate the clearance rates of the target OPEs, hepatic clearance rates (CLh) of OPEs were extrapolated from their in vitro intrinsic clearance data in human liver microsomes (CLHLM). The calculated CLh values of TCEP and TDCIPP were comparable to their CLrenal, indicating that the in vitro extrapolation method was suitable for estimating the clearance rates of OPEs. The higher binding affinity of TDCIPP with plasma proteins could reduce its renal clearance. The estimated half-lives of Cl-OPEs in human were longer than those of the aryl- and alkyl-OPEs. This study provided a feasible in vitro method to predict the clearance and half-lives of OPEs in human, which is significant for their accurate health risk assessment. Keywords: Organophosphate esters, Organophosphate diester metabolites, Renal clearance, Hepatic clearance, Half-life