Abstract

The disposition and metabolism of prinomide, the 1:1 triethanolamine salt of 1-methyl-beta-oxo-alpha-(phenylcarbamoyl)-2-pyrrolepropionitrile (CGS 10787B), have been investigated in a number of animal species after single and multiple oral dosing with 14C-labeled and unlabeled drug. After single oral doses of 25 to 50 mg/kg of [14C]prinomide to mice, rats, hamsters, dogs, cynomolgus monkeys, and baboons, radioactivity was excreted primarily in urine, in the form of metabolites. However, in the mouse and monkey, fecal excretion was also significant. In the cynomolgus monkey, a radioactive dose of drug administered after multiple doses of unlabeled drug gave rise to peak plasma concentrations of radioactivity within 1 to 6 hr. Prinomide accounted for approximately 69% of this radioactivity. The terminal plasma half-life of the drug was 24 to 41 hr. Studies in rats with [14C]prinomide indicated that radioactivity was distributed rapidly to all tissues, with the highest levels being observed in blood and well perfused organs and tissues. The lowest levels were detected in fat, eyes, and brain. Tissue levels declined to less than 6% of peak values by 48 hr after dosing, the only exceptions being fat and kidney, which retained 14 and 17% of peak radioactivity, respectively. The metabolism of prinomide was qualitatively similar in all species investigated. Major metabolites identified were the phenyl ring p-hydroxy, M1, and the bicyclic spiro, M2, derivatives of the parent drug. Other common metabolites were M3, the phenyl ring p-hydroxy analog of M2 and a complete rearrangement product in the form of a succinimide derivative, M4.(ABSTRACT TRUNCATED AT 250 WORDS)