Ketorolac tromethamine absorption, distribution, metabolism, excretion, and pharmacokinetics in animals and humans

Abstract

Ketorolac tromethamine (KT), a potent non-narcotic analgesic, with cyclooxygenase inhibitory activity, was administered (14C-labeled and unlabeled) intravenously (iv), orally (po), and intramuscularly (im) in solution to humans, cynomolgus monkeys, rabbits, rats, and mice. KT was absorbed rapidly (Tmax less than 1.0 hr) and efficiently (greater than 87%) following po and im doses in all species. The plasma half-life of ketorolac (K) ranged from 1.1 hr (rabbits) to 6.0 hr (humans). The protein binding of K ranged from 72.0% (mouse) to 99.2% (humans). Linear pharmacokinetics of K was observed in the mouse after single oral doses of KT ranging from 0.25 to 16 mg/kg. Radioactivity was excreted predominantly into urine, ranging from 78.9% (mouse) to 102% (monkey) following iv doses. The dose was excreted into urine primarily as K conjugates, K, and p-hydroxy-K in humans. The monkey was similar to humans with respect to kinetics, but did not form the p-hydroxy metabolite. The rabbit was unusual in that it exhibited substantial presystemic metabolism (50%). The rat excreted a much higher percentage of radioactivity into the feces and formed an additional unidentified metabolite. The most comparable species with respect to humans metabolically was the mouse. The metabolism and excretion of K was similar following iv, po, and im doses within each species studied.