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 matrix metalloproteinases (MMP) inhibitors known as thiadiazoles, was found to be quickly eliminated from rats. A major metabolite (approximately 10% of total dose) was found to be present in the bile of rats. The metabolite in question was isolated and purified from the bile fluids collected from six cannulated rats. From a total of approximately 75 mg of PNU-107859 administered to rats, 3.3 mg of the metabolite was recovered. The NMR and mass spectrometry results indicated that the metabolite is a glucuronide conjugate (1-deoxy-1beta-substituted D-glucopyranosiduronic acid) of the intact drug. Furthermore, the UV, MS, and NMR data established that the conjugate is located at the nitrogen alpha to the thiocarbonyl of the thiadiazole ring.

[1]  A. H. Drummond,et al.  Processing of tumour necrosis factor-α precursor by metalloproteinases , 1994, Nature.

[2]  M. Gerhart,et al.  Protection against a lethal dose of endotoxin by an inhibitor of tumour necrosis factor processing , 1994, Nature.

[3]  W. H. Schaefer.  Formation of a carbamoyl glucuronide conjugate of carvedilol in vitro using dog and rat liver microsomes. , 1992, Drug metabolism and disposition: the biological fate of chemicals.

[4]  A. Henney,et al.  Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[5]  J. Powell,et al.  Metalloproteinases in degenerative aortic disease. , 1991, Clinical science.

[6]  J. Vilček,et al.  Tumor necrosis factor. New insights into the molecular mechanisms of its multiple actions. , 1991, The Journal of biological chemistry.

[7]  M. Tarbit,et al.  Characterization of a quaternary, N-glucuronide metabolite of the imidazole antifungal, tioconazole. , 1990, Drug metabolism and disposition: the biological fate of chemicals.

[8]  G. Murphy,et al.  The tissue metalloproteinase family and the inhibitor TIMP: a study using cDNAs and recombinant proteins. , 1990, Annals of the rheumatic diseases.

[9]  W. L. Nelson,et al.  Synthesis and identification of the N-glucuronides of norgallopamil and norverapamil, unusual metabolites of gallopamil and verapamil. , 1990, The Journal of pharmacology and experimental therapeutics.

[10]  C. Overall,et al.  Demonstration of tissue collagenase activity in vivo and its relationship to inflammation severity in human gingiva. , 1987, Journal of periodontal research.

[11]  D. Staiger,et al.  Structural assignment of an N-glucuronide metabolite of the phenylethanolamine N-methyltransferase (PNMT) inhibitor 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide by 15N-NMR. , 1986, Biochemical pharmacology.

[12]  K. Mohri,et al.  Bucolome N-glucuronide: purification and identification of a major metabolite of bucolome in rat bile. , 1985, Xenobiotica; the fate of foreign compounds in biological systems.

[13]  Y. Sanno,et al.  Studies on antianaphylactic agents. 6. Synthesis of some metabolites of 6-ethyl-3-(1H-tetrazol-5-yl)chromone and their analogues. , 1979, Journal of medicinal chemistry.