title: A strategy to reduce biliary clearance in early drug discovery.
abstract: BACKGROUND
  Biliary excretion can modulate the pharmacokinetic profile of drug candidates, and may represent a liability for drug-drug interactions. This study proposes a strategy to reduce biliary clearance using the efflux ratio in Caco-2 cells in parallel to an abbreviated pharmacokinetic study in bile duct-cannulated rats (BDC).
  
  
  METHODS
  Apical to basolateral (A to B) and basolateral to apical (B to A) permeability of 20 new chemical entities (NCEs) were determined in a 24-well permeability assay. In parallel, biliary excretion was determined in an abbreviated format in BDC rats. Test compounds were administered via an intravenous dose of 1 mg/kg and the percentage (%) of parent compound excreted in the bile in the first 3 hours after dosing was determined by LC-MS/MS analysis.
  
  
  RESULTS
  A reasonably good correlation (r(2)=0.635) between the in vitro efflux ratio from the Caco-2 assay and in vivo biliary excretion of parent compound in BDC rats was observed. All seven compounds with an efflux ratio of <5 had less than 25% of the parent excreted in rat bile. In contrast, 3 out of the 13 compounds with an efflux ratio >5 had less than 25% of the dose excreted in rat bile.
  
  
  CONCLUSIONS
  This suggests that a compound with an efflux ratio of <5 is at lower risk of having significant biliary clearance and that Caco-2 efflux ratio obtained from a high throughput screening assay may be used as an early indicator of biliary excretion. Although, we propose to reduce the occurrence of false positive prediction for biliary clearance (23%) by performing abbreviated PK in BDC rats for compounds with high efflux ratio.
authors.affiliation: Department of Biological Sciences, Boehringer-Ingelheim (Canada) Ltd., Research and Development, 2100 Cunard Street, Laval, Québec H7S 2G5, Canada. Electronic address: RESGeneral.LAV@boehringer-ingelheim.com.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux
authors.forename: Edith
authors.initials: E
authors.lastname: Bellavance
authors.forename: Hugo
authors.initials: H
authors.lastname: Poirier
authors.forename: Mariève
authors.initials: M
authors.lastname: Dupuis
authors.forename: Michel
authors.initials: M
authors.lastname: Garneau
authors.forename: Maria D
authors.initials: MD
authors.lastname: Ribadeneira
authors.forename: Jianmin
authors.initials: J
authors.lastname: Duan
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism*; D018938:Caco-2 Cells; D002853:Chromatography, Liquid / Q000379:methods; D015195:Drug Design; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D004364:Pharmaceutical Preparations
keywords: Bile-duct cannulated rats; Biliary excretion; Caco-2 cells; Efflux; Methods