Estimation of Biliary Excretion of Foreign Compounds Using Properties of Molecular Structure

Abstract

Abstract. Biliary excretion is one of the main elimination pathways for drugs and/or their metabolites. Therefore, an insight into the structural profile of cholephilic compounds through accurate modelling of the biliary excretion is important for the estimation of clinical pharmacokinetics in early stages of drug discovery. The aim of this study was to develop quantitative structure-activity relationships as computational tools for the estimation of biliary excretion and identification of the molecular properties controlling this process. The study used percentage of dose excreted intact into bile measured in vivo in rat for a diverse dataset of 217 compounds. Statistical techniques were multiple linear regression analysis, regression trees, random forest and boosted trees. A simple regression tree model generated using the CART algorithm was the most accurate in the estimation of the percentage of bile excretion of compounds, and this outperformed the more sophisticated boosted trees and random forest techniques. Analysis of the outliers indicated that the models perform best when lipophilicity is not too extreme (log P<5.35) and for compounds with molecular weight above 280 Da. Molecular descriptors selected by all these models including the top ten incorporated in boosted trees and random forest indicated a higher biliary excretion for relatively hydrophilic compounds especially if they are anionic or cationic, and have a large molecular size. A statistically validated molecular weight threshold for potentially significant biliary excretion was above 348 Da.

Effect of OATP-binding on the prediction of biliary excretion

“…Table 8 provides the statistical parameters of the interactive regression trees. high dipole moment (AM1_dipole) in biliary excretion was also seen in our previous study (Sharifi and Ghafourian, 2014). Statistical parameters of the model can be seen in Table 8.…”

“…The study used two datasets: 1) percentage of dose excreted intact into bile in rat (BE%) for 217 compounds (Yang el al., 2009, Sharifi andGhafourian, 2014); 2) percentage inhibition of OATP transporters, OATP1B1, OATP1B3 and OATP2B1 (Karlgren et al, 2012a). Table 1 gives a summary of the datasets.…”

“…In general, large molecular weight requirement is the most well-known molecular attribute associated with biliary excretion, although the actual molecular weight threshold for effective biliary excretion has been debated (Sharifi and Ghafourian, 2014;Yang et al, 2009;Varma et al, 2012;Luo et al, 2010). In a related context, several structural fragments have been implicated in high biliary excretion.…”

“…In a related context, several structural fragments have been implicated in high biliary excretion. Examples of such fragments include glucuronide and sulphate groups that may be added during phase II metabolism and then the large conjugated metabolites that are mainly hydrophilic may be readily excreted through bile (Kullak-Ublick et al, 2000;Sharifi and Ghafourian, 2014). Carboxylic acid groups (COOH) have also been linked with high biliary excretion in a recent quantitative structure activity relationship study (QSAR) (Luo et al, 2010).…”

“…Quantitative prediction of biliary excretion of compounds has been investigated in several recent publications employing various QSAR techniques (Chen et al 2010, Luo et al, 2010Yang et al, 2009, Sharifi andGhafourian, 2014;Hosey et al, 2014). It is believed that the development of a reliable structure-activity model for the prediction of cholephilic compounds is not an easy task (Gandhi and Morris, 2012;Hosey et al, 2014).…”