The metabolic disposition of acifran, a new antihyperlipidemic agent, in rats and dogs

1. The metabolic disposition of the antihyperlipidemic agent acifran (AY-25, 712) was determined in rats and dogs. The synthesis of 14C-labelled acifran is described. 2. Serum levels of 14C and acifran were measured in rats and dogs after p.o. and i.v. administration of 14C-acifran at a dose of 10 mg/kg. Over 80% of the 14C in serum was due to acifran. The drug was rapidly absorbed and the pharmacokinetics, unaffected by increasing the dose or by daily multiple doses, were characterized by a two-compartment open model. Food reduced the bioavailability of acifran by 27% in the dog. About 65% of the dose was absorbed in rats, and at least 88% in dogs. The elimination t1/2 of acifran from serum was 1.5 h in the rat and 3 h in the dog. 3. Acifran was partially bound to serum proteins, man > rat > dog; the drug was found to displace protein-bound warfarin in rat and dog, but not in human serum. 4. Radioactivity did not tend to accumulate in tissues, except for the kidney, where the 14C concentration was five times higher than in the serum; elimination of 14C from all the tissues was similar to that from serum. 5. Most of the absorbed dose was excreted in the urine. Acifran did not undergo enterohepatic circulation in the rat. Virtually all the urinary 14C in both species was due to the unchanged compound. 6. In conclusion, the disposition of acifran was similar in rats and dogs. The drug was rapidly absorbed and eliminated, and underwent no detectable biotransformation. There was no tissue retention and excretion was mainly in the urine.