THE PHARMACOKINETICS AND METABOLISM OF DUP 532, A NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONIST, IN RATS AND DOGS

DuP 532, tafluoroethyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4- yl]methyl] imidazole-5-carboxylic acid, is an orally active, non-peptide angiote nsin II (AII) receptor antagonist. DuP 532 is more potent and longer a cting than losartan, another AII receptor antagonist currently undergo ing phase III clinical trials. The pharmacokinetics and the effect of the salt form on the bioavailability of DuP 532 were determined in rat s and dogs. In rats, the absolute oral bioavailability and half-life a veraged 8.0% and 3.5 h, respectively, after the sodium bicarbonate sol ution and 7.6% and 3.6 h, respectively, after the methyl cellulose sus pension. In dogs, the absolute oral bioavailability averaged 13.4% aft er the sodium bicarbonate solution and 11.9% after hard gelatin capsul es containing the neat powder. The data demonstrated that there were n o differences in bioavailability between the free acid and the sodium salt of DuP 532 after oral administration to rats and dogs. The in vit ro metabolism of C-14-DuP 532 was evaluated with rat, dog, and human l iver microsomes. HPLC analyses with UV and radiochemical flow detectio n showed that recovery of DuP 532 was greater than 99%, suggesting tha t there was little if any metabolism by liver microsomal enzymes. Ther efore, the low oral bioavailability in rats was probably due to poor a bsorption of DuP 532 from the GI tract rather than extensive metabolis m.