Plasma and tissue levels of furosemide in dogs and monkeys following single and multiple oral doses.
35S-Furosemide was administered to beagle dogs and rhesus monkeys as an oral solution on a single and a 20 repeated 5 mg/kg/day dosing regimen. In both species, furosemide is rapidly but incompletely absorbed with peak plasma levels being achieved within one hour after dosing. The plasma level versus time profiles do not appear to be significantly altered as a result of the repetitive dosing regimen employed, although the profiles themselves are quite different for the two species studied. Following single oral doses, the observed peak plasma levels achieved in dogs are approximately eight-fold higher than in monkeys. In dogs, oral administration of furosemide results in a biexponential disposition curve while in monkeys the profile appears monoexponential. The major disposition phase in dogs has a half-life or approximately 30 minutes and is followed by a slow elimination phase with a half-life of approximately 7 hours. Only a small percentage of the absorbed dose is affected by the slow disposition phase and consequently accumulation of furosemide on the once-daily dosing regimen is slight. In the monkey studies, the rapid disposition phase was not observed and the slow disposition phase had a half-life of approximately 11 hours. On the repetitive dosing regimen, the monkey appeared to accumulate furosemide to a slightly greater extnet than the dog and showed a lesser degree of fluctuation within a dosing interval. In both species, liver and kidney radioactivity levels were not detectable three days after a single dose although low levels of furosemide and/or metabolites were observed for six days following the last dose of the multiple dosing regimen. At the dosage level and regimen employed, no unusual or "typical" lesions associated with furosemide were found in the dog and monkey tissues examined histopathologically.