Isolation and identification of a major metabolite of PNU-107859, an MMP inhibitor from the biliary fluid of rats

PNU-107859, an important representative structure in a novel class of matri x metalloproteinases (MMP) inhibitors known as thiadiazoles, was found to b e quickly eliminated from rats. A major metabolite (approximately 10% of to tal dose) was found to be present in the bile of rats. The metabolite in qu estion was isolated and purified from the bile fluids collected from six ca nnulated rats. From a total of approximately 75 mg of PNU-107859 administer ed to rats, 3.3 mg of the metabolite was recovered. The NMR and mass spectr ometry results indicated that the metabolite is a glucuronide conjugate (1- deoxy-1 beta-substituted D-glucopyranosiduronic acid) of the intact drug. F urthermore, the UV, MS, and NMR data established that the conjugate is loca ted at the nitrogen alpha to the thiocarbonyl of the thiadiazole ring.