In Silico Prediction of Biliary Excretion of Drugs in Rats Based on Physicochemical Properties

Luo, Gang; Johnson, Stephen R.; Hsueh, Mei-Mann; Zheng, Joanna J.; Cai, Hong; Xin, Baomin; Chong, Samuel S.; He, Kan; Harper, Timothy W.

doi:10.1124/dmd.108.026260

Cited by 32 publications

(34 citation statements)

References 31 publications

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“…Their study and others implicated hydrogen bond interactions (5,27), charge state (5,27,28), the presence of polar groups or a large polar surface area (5,(27)(28)(29)(30), and the presence of dipole or quadrupole moments (27,28), while others have implicated hydrophilicity (5,28,30), carboxylic acid groups (28,29), and rotatable bonds (5,29).…”

Section: Introductionmentioning

confidence: 99%

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

Hosey-Cojocari

Broccatelli

Benet

2014

AAPS J

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Abstract. Biliary excretion is an important route of elimination for many drugs, yet measuring the extent of biliary elimination is difficult, invasive, and variable. Biliary elimination has been quantified for few drugs with a limited number of subjects, who are often diseased patients. An accurate prediction of which drugs or new molecular entities are significantly eliminated in the bile may predict potential drug-drug interactions, pharmacokinetics, and toxicities. The Biopharmaceutics Drug Disposition Classification System (BDDCS) characterizes significant routes of drug elimination, identifies potential transporter effects, and is useful in understanding drug-drug interactions. Class 1 and 2 drugs are primarily eliminated in humans via metabolism and will not exhibit significant biliary excretion of parent compound. In contrast, class 3 and 4 drugs are primarily excreted unchanged in the urine or bile. Here, we characterize the significant elimination route of 105 orally administered class 3 and 4 drugs. We introduce and validate a novel model, predicting significant biliary elimination using a simple classification scheme. The model is accurate for 83% of 30 drugs collected after model development. The model corroborates the observation that biliarily eliminated drugs have high molecular weights, while demonstrating the necessity of considering route of administration and extent of metabolism when predicting biliary excretion. Interestingly, a predictor of potential metabolism significantly improves predictions of major elimination routes of poorly metabolized drugs. This model successfully predicts the major elimination route for poorly permeable/poorly metabolized drugs and may be applied prior to human dosing.

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Section: Introductionmentioning

confidence: 99%

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

Hosey-Cojocari

Broccatelli

Benet

2014

AAPS J

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“…However, limited information exists on the ability of these models to predict human biliary disposition, primarily because of the absence of systematic clinical studies measuring the rate and extent of biliary elimination of drugs (Roberts et al, 2002;Ghibellini et al, 2006;Lavé et al, 2009). Therefore, despite the species differences and potential difficulties in extrapolating BE, the bile-duct-cannulated (BDC) rat model is often used for assessing biliary elimination (Yang et al, 2009;Luo et al, 2010). Unfortunately, this model is less amenable for generating data for a large number of compounds to support drug design efforts in the discovery setting, because of time-consuming and complicated protocols.…”

Section: Introductionmentioning

confidence: 99%

Physicochemical Property Space of Hepatobiliary Transport and Computational Models for Predicting Rat Biliary Excretion

Varma

Chang²,

Lai³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Biliary excretion (BE) is a major elimination pathway, and its prediction is particularly important for optimization of systemic and/or target-site exposure of new molecular entities. The objective is to characterize the physicochemical space associated with hepatobiliary transport and rat BE and to develop in silico models. BE of 123 in-house compounds was obtained using the bile-duct cannulated rat model. Human and rat hepatic uptake transporters (hOATP1B1, hOATP1B3, hOATP2B1, and rOatp1b2) substrates (n ‫؍‬ 183) were identified using transfected cells. Furthermore, the datasets were extended by adding BE of 163 compounds and 97 organic anion transporting polypeptide (OATP) substrates from the literature. Approximately 60% of compounds showing percentage of BE (%BE) > 10 are anions, with mean BE of anions (36%) more than 3-fold higher than that of nonacids (11%). Compounds with %BE > 10 are found to have high molecular mass, large polar surface area, more rotatable bonds, and high H-bond count, whereas the lipophilicity and passive membrane permeability are lower compared with compounds with %BE < 10. According to statistical analysis and principal component analysis, hOATPs and rOatp1b2 substrates showed physicochemical characteristics that were similar to those of the %BE > 10 dataset. We further build categorical in silico models to predict rat BE, and the models (gradient boosting machine and scoring function) developed showed 80% predictability in identifying the rat BE bins (%BE > 10 or < 10). In conclusion, the significant overlap of the property space of OATP substrates and rat BE suggests a predominant role of sinusoidal uptake transporters in biliary elimination. Categorical in silico models to predict rat BE were developed, and successful predictions were achieved.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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Effect of OATP-binding on the prediction of biliary excretion

Sharifi

Ghafourian

2016

Xenobiotica

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Article (Accepted Version) http://sro.sussex.ac.uk Sharifi, Mohsen and Ghafourian, Taravat (2017) Effect of OATP-binding on the prediction of biliary excretion. Xenobiotica, 47 (7). pp. [614][615][616][617][618][619][620][621][622][623][624][625][626][627][628][629][630][631] This version is available from Sussex Research Online: http://sro.sussex.ac.uk/64120/ This document is made available in accordance with publisher policies and may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the URL above for details on accessing the published version. Copyright and reuse:Sussex Research Online is a digital repository of the research output of the University.Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable, the material made available in SRO has been checked for eligibility before being made available.Copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. The results indicated that incorporation of predicted OATP inhibition improves accuracy of biliary excretion models. The best result was obtained from a simple regression tree that used predicted OATP1B1 percentage inhibition at the root node of the tree. Effect of OATP-binding on the prediction of biliary excretion

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In Silico Prediction of Biliary Excretion of Drugs in Rats Based on Physicochemical Properties

Cited by 32 publications

References 31 publications

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

Physicochemical Property Space of Hepatobiliary Transport and Computational Models for Predicting Rat Biliary Excretion

Effect of OATP-binding on the prediction of biliary excretion

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