Document Detail


Physicochemical Property Space of Hepato-biliary Transport and Computational Models for Predicting Rat Biliary Excretion.
MedLine Citation:
PMID:  22580868     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Biliary excretion 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 hepato-biliary transport and rat biliary excretion (BE) and develop in silico models. BE of 123 in-house (Pfizer, Inc.) compounds was obtained utilizing bile-duct cannulated (BDC) 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 OATPs substrates from literature. About 60% of compounds showing %BE≥10 are anions, with mean BE of anions (36%) more than three-fold higher than that of non-acids (11%). Compounds with %BE≥10 are found to have high MW, large PSA and more RB and H-bond count; while the lipophilicity and passive membrane permeability are lower compared to compounds with %BE<10. Interestingly, based on statistical analysis and principal component analysis, hOATPs and rOatp1b2 substrates showed similar physicochemical characteristics as that of %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≥or <10). In conclusion, the significant overlap of the property space of OATPs substrates and rat BE suggests predominant role of sinusoidal uptake transporters in biliary elimination. Categorical in silico models to predict rat BE were developed, and successful predictions were achieved.
Authors:
Manthena V S Varma; George Chang; Yurong Lai; Bo Feng; Ayman F El-Kattan; John Litchfield; Theunis C Goosen
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-5-11
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  -     ISSN:  1521-009X     ISO Abbreviation:  -     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-5-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Pfizer, Inc.
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