In silico prediction of biliary excretion of drugs in rats based on physicochemical properties.
Evaluating biliary excretion, a major elimination pathway for many compounds, is important in drug discovery. The bile duct-cannulated (BDC) rat model is commonly used to determine the percentage of dose excreted as intact parent into bile. However, a study using BDC rats is time-consuming and cost-ineffective. The present report describes a computational model that has been established to predict biliary excretion of intact parent in rats as a percentage of dose. The model was based on biliary excretion data of 50 Bristol-Myers Squibb Co. compounds with diverse chemical structures. The compounds were given intravenously at <10 mg/kg to BDC rats, and bile was collected for at least 8 h after dosing. Recoveries of intact parents in bile were determined by liquid chromatography with tandem mass spectrometry. Biliary excretion was found to have a fairly good correlation with polar surface area (r = 0.76) and with free energy of aqueous solvation (DeltaG(solv aq)) (r = -0.67). In addition, biliary excretion was also highly corrected with the presence of a carboxylic acid moiety in the test compounds (r = 0.87). An equation to calculate biliary excretion in rats was then established based on physiochemical properties via a multiple linear regression. This model successfully predicted rat biliary excretion for 50 BMS compounds (r = 0.94) and for 25 previously reported compounds (r = 0.86) whose structures are markedly different from those of the 50 BMS compounds. Additional calculations were conducted to verify the reliability of this computation model.
Luo
Gang
G
Pharmaceutical Candidate Optimization-Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, Pennington, New Jersey 08534, USA.
Johnson
Stephen
S
Hsueh
Mei-Mann
MM
Zheng
Joanna
J
Cai
Hong
H
Xin
Baomin
B
Chong
Saeho
S
He
Kan
K
Harper
Timothy W
TW
D000818:Animals; D001646:Bile / Q000737:chemistry / Q000378:metabolism*; D001652:Bile Ducts; D002264:Carboxylic Acids / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics; D002408:Catheters, Indwelling; D055598:Chemical Phenomena; D019295:Computational Biology; D015507:Drugs, Investigational / Q000032:analysis / Q000737:chemistry* / Q000493:pharmacokinetics*; D005103:Expert Systems; D016018:Least-Squares Analysis; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013499:Surface Properties
D002264:Carboxylic Acids; D015507:Drugs, Investigational