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Comparative Pharmacokinetics of [ 14 C]Metosulam ( N ‐[2,6‐Dichloro‐3‐methylphenyl]‐5,7‐dimethoxy‐1,2,4‐triazolo‐[1,5 a ]‐pyrimidine‐2‐sulfonamide) in Rats, Mice and Dogs
Author(s) -
Timchalk C.,
Dryzga M. D.,
Johnson K. A.,
Eddy S. L.,
Freshour N. L.,
Kropscott B. E.,
Nolan R. J.
Publication year - 1997
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/(sici)1099-1263(199701)17:1<9::aid-jat390>3.0.co;2-s
Subject(s) - beagle , pharmacokinetics , urine , feces , pharmacology , dosing , chemistry , pyrimidine , oral administration , absorption (acoustics) , sulfonamide , toxicity , medicine , biology , biochemistry , stereochemistry , paleontology , physics , acoustics
This study was conducted to provide data on the pharmacokinetics of [ 14 C]metosulam ( N ‐[2,6‐dichloro‐3‐methylphenyl]‐5,7‐dimethoxy‐1,2,4‐triazolo‐[1,5 a ]‐[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 [ 14 C]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 14 C activity and selected tissues were evaluated for localization of 14 C activity by histoautoradiography. Selected urine and plasma specimens were also profiled for metabolites by high‐performance liquid chromatography. [ 14 C]Metosulam was absorbed rapidly ( t 1/2 < 1 h) in all three species. Mice and dogs absorbed ca. 20% of the orally administered dose of [ 14 C]metosulam, compared to >70% absorption in the rat. Analysis of 14 C 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 14 C localization in the kidneys of dogs or in the eyes of rats. In rats and mice the 14 C 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 t 1/2 of 73 h. In all three species, [ 14 C]metosulam and metabolites were excreted in the urine and quantitatively the relative amount of [ 14 C]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.