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Comparative Pharmacokinetics of [14C]Metosulam (N‐[2,6‐Dichloro‐3‐methylphenyl]‐5,7‐dimethoxy‐1,2,4‐triazolo‐[1,5a]‐pyrimidine‐2‐sulfonamide) in Rats, Mice and Dogs

This study was conducted to provide data on the pharmacokinetics of [14C]metosulam (N‐[2,6‐dichloro‐3‐methylphenyl]‐5,7‐dimethoxy‐1,2,4‐triazolo‐[1,5a]‐[pyrimidine‐2‐sulfonamide). Groups of male Sprague‐Dawley rats, CD‐1 mice and Beagle dogs were given a single oral gavage dose of 100 mg [14C]metosulam kg−1 body weight and blood, urine, feces and selected tissue specimens were collected up to 168 h for rats and mice and 216 h post‐dosing for dogs. Two of these dogs received a second 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 administered an intravenous dose of 1 mg kg−1 and plasma, urine and feces were collected for 72 h post‐dosing. Specified tissue specimens were analyzed for 14C activity and selected tissues were evaluated for localization of 14C activity by histoautoradiography. Selected urine and plasma specimens were also profiled for metabolites by high‐performance liquid chromatography. [14C]Metosulam was absorbed rapidly (t1/2 < 1 h) in all three species. Mice and dogs absorbed ca. 20% of the orally administered dose of [14C]metosulam, compared to >70% absorption in the rat. Analysis of 14C activity and histoautoradiography of the dog eyes indicated that the retina, a target for toxicity in the dog, did exhibit affinity for the radiotracer. There was no evidence of 14C localization in the kidneys of dogs or in the eyes of rats. In rats and mice the 14C plasma time‐course was fit to a two‐compartment pharmacokinetic model, whereas the dog was fit to a one‐compartment model. The half‐lives for the rapid initial (α) and slower terminal phases (β) were 9 h and 60 h for the rat and 20 h and 155 h for mice, respectively. The dog had an elimination t1/2 of 73 h. In all three species, [14C]metosulam and metabolites were excreted in the urine and quantitatively the relative amount of [14C]metosulam metabolism followed the pattern of mice > rats > dogs. These data suggest that the observed ocular lesion in dogs is due to metosulam and may in part be due to its selective affinity for the dog retina. © 1997 by John Wiley & Sons, Ltd.