Metabolic disposition of CI-924, a new lipid regulating agent, in laboratory animals

The disposition of carbon-14 labeled CI-924 (I), 5,5'-[1,1-biphenyl]-2,5 diyl-bis(oxy)-bis-2,2'-dimethylpentanoic acid, was studied in beagle dogs and rats following single 10 mg/kg po doses. Serial plasma, urine and fecal samples were collected up to 168 hr and analyzed for total radioactivity. Peak 14C plasma concentrations of 31 mcg/ml (dogs) and 66 mcg/ml (rats) were attained within 0.5 and 1.0 hr after dosing. The concentrations declined thereafter with estimated half life of 11 and 5 hr in rats and dogs, respectively. TLC radiochromatography revealed that I was the only component in circulating blood. Tissue distribution study in rats showed that the highest 14C concentrations were found in plasma and liver with decreasing concentrations in lung, heart, kidney, skin, gonads, spleen, fat, muscle, adrenals, and brain. All tissue concentrations declined in parallel with plasma levels with half lives of 14-22 hr. Urinary and fecal excretion accounted for 1-3% and 92-96% of the dose, respectively. Balance study in bile duct cannulated rats showed that 90%, 1%, and 1% of the dose was excreted in bile, urine, and feces. Unchanged drug and varying amounts of its conjugate were the only products present in bile, urine or feces. These results indicate that I was completely absorbed and eliminated primarily by biliary excretion in the form of unchanged drug and its conjugate