Structure-pharmacokinetic relationship of in vivo rat biliary excretion.
Accurately measuring and predicting biliary excretion would be extremely valuable in evaluating the contribution of biliary excretion to the total systemic clearance, understanding potential mechanisms of hepatobiliary toxicity as well as potentials for drug-drug interactions in drug discovery. In this study, in vivo rat biliary excretion of drug-like molecules was measured using bile duct cannulated rats. Literature biliary excretion data with similar experimental conditions were collected. A predictive quantitative structure-pharmacokinetic relationship (QSPR) model was developed using genetic algorithm guided principal component regression analysis and 2D molecular descriptors. In the derived model, hydrophobicity expressed with calculated distribution coefficients (cLogD) is the most important molecular property correlating biliary excretion. The derived model has been validated using literature data, and should be useful in estimating biliary excretion potentials of molecules in drug discovery.
Chen
Yue
Y
Pfizer Global Research and Development, Groton Laboratories, 558 Eastern Point Road, Groton, CT 06340, USA.
Cameron
Kimberly
K
Guzman-Perez
Angel
A
Perry
David
D
Li
Dong
D
Gao
Hua
H
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001652:Bile Ducts / Q000378:metabolism*; D001659:Biliary Tract / Q000378:metabolism*; D002478:Cells, Cultured; D004337:Drug Carriers; D004347:Drug Interactions / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D008657:Metabolic Clearance Rate / Q000502:physiology; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014018:Tissue Distribution
D018528:ATP-Binding Cassette Transporters; D004337:Drug Carriers; D004364:Pharmaceutical Preparations