COMPARATIVE PHARMACOKINETICS OF [C-14] METOSULAM 2,4-TRIAZOLO-[1,5-ALPHA]-PYRIMIDINE-2-SULFONAMIDE) IN RATS, MICE AND DOGS

This study was conducted to provide data on the pharmacokinetics of [C -14]metosulam (N-[2,6-dichloro-3-methylphenyl]-5,7-dimethoxy- 1,2,4-tr iazolo-[1,5a]-[pyrimidine-2-sulfonamide). Groups of male Sprague-Dawle y rats, CD-1 mice and Beagle dogs were given a single oral gavage dose of 100mg [C-14]metosulam kg(-1) body weight and blood, urine, feces a nd selected tissue specimens were collected up to 168 h for rats and m ice and 216 h post-dosing for dogs. Two of these dogs received a secon d oral dose of 100 mg kg(-1) and were humanely euthanized at 12 h post -dosing and selected tissues were collected. The third dog was adminis tered an intravenous dose of 1 mg kg(-1) and plasma, urine and feces w ere collected for 72 h post-dosing. Specified tissue specimens were an alyzed for C-14 activity and selected tissues were evaluated for local ization of C-14 activity by histoautoradiography. Selected urine and p lasma specimens were also profiled for metabolites by high-performance liquid chromatography. [C-14]Metosulam was absorbed rapidly (t(1/2) < 1 h) in all three species. Mice and dogs absorbed ca. 20% of the orall y administered dose of [C-14]metosulam, compared to >70% absorption in the rat. Analysis of C-14 activity and histoautoradiography of the do g eyes indicated that the retina, a target for toxicity in the dog, di d exhibit affinity for the radiotracer. There was no evidence of C-14 localization in the kidneys of dogs or in the eyes of rats. In rats an d mice the C-14 plasma time-course was fit to a two-compartment pharma cokinetic model, whereas the dog was fit to a one-compartment model. T he half-lives for the rapid initial (alpha) and slower terminal phases (beta) were 9 h and 60 h for the rat and 20 h and 155 h for mice, res pectively. The dog had an elimination t(1/2) Of 73 h. In all three spe cies, [C-14]metosulam and metabolites were excreted in the urine and q uantitatively the relative amount of [C-14]metosulam metabolism follow ed the pattern of mice > rats > dogs. These data suggest that the obse rved ocular lesion in dogs is due to metosulam and may in part be due to its selective affinity for the dog retina. (C) 1996 by John Wiley & Sons, Ltd.