A strategy to reduce biliary clearance in early drug discovery.

Introduction: 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.

Discussion: 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.