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A quantitative threshold for high/low extent of urinary excretion of compounds in humans
Author(s) -
Dave Rutwij A.,
Morris Marilyn E.
Publication year - 2016
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2013
Subject(s) - threshold limit value , chemistry , receiver operating characteristic , urine , biological system , statistics , mathematics , biochemistry , organic chemistry , biology
Abstract In this study, a quantitative threshold was determined for the high/low extent of urinary excretion (UE) of compounds in humans, using a straightforward but robust statistical method known as receiver operating characteristic curve (ROC) analysis, and also 18 potential physicochemical determinants of UE were evaluated. Data on the percent of drug excreted unchanged into the urine, % A e , were used to determine the threshold for high/low UE. Compounds can be divided into high/low UE groups using the threshold value of A e = 16.8%, namely those with A e > 16.8% are classified as high UE and those with A e ≤ 16.8% as low UE. The % A e negatively correlated with cLog P ( r = −0.56); however, cLog P could not quantitatively predict the value of % A e ( R 2 adj. = 0.32). Several determinants of the extent of UE, including cLog P , ACD labs cLog P and ACD labs cLog D (pH=7.4) , were successfully evaluated as a priori indicators of the extent of UE using two cut‐off values for each parameter. Moreover, 87% of the 90 compounds in the external validation set were correctly classified using this approach. Analysis of the physicochemical spaces of compounds in these two groups showed significant overlap, which hinders the a priori determination of the extent of UE of compounds using a single threshold/cut‐off value of simple physicochemical parameters. In conclusion, 16.8% is a quantitative threshold value to distinguish between high and low UE and new molecular entities with cLog P and ACD labs cLog P values of ≤0.7 and ≥1.0 and ACD labs cLog D (pH=7.4) values of ≤0.0 and ≥0.5 could be identified as exhibiting high and low UE, respectively. Copyright © 2016 John Wiley & Sons, Ltd.