Metabolism of [(1)(4)C]prometryn in rats.

[(1)(4)C]Prometryn, 2, 4-bis(isopropylamino)-6-(methylthio)-s-triazine, was orally administered to male and female rats at approximately 0.5 and 500 mg/kg; daily urine and feces were collected. After 3 or 7 days rats were sacrificed, and blood and selected tissues were isolated. The urine and feces extracts were characterized for metabolite similarity as well as for metabolite identification. Over 30 metabolites were observed, and of these, 28 were identified mostly by mass spectrometry and/or cochromatography with available reference standards. The metabolism of prometryn was shown to occur by N-demethylation, S-oxidation, S-S dimerization, OH substitution for NH(2) and SCH(3), and conjugation with glutathione or glucuronic acid. Rat liver microsomal incubations of prometryn were conducted and compared to the in vivo metabolism. Both in vivo and in vitro phase I metabolisms of prometryn were similar, with S-oxidation and N-dealkylation predominating. The involvement of cytochrome P-450 and flavin-containing monooxidase in the in vitro metabolism of prometryn was investigated.

Disposition and metabolism of prinomide in laboratory animals.

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)

Metabolism of aminoglutethimide in the rat.

The metabolism of aminoglutethimide was studied in the rat by use of the 14C-labeled compound. Following oral doses of 5 and 50 mg/kg, the drug was almost completely eliminated within 48 hr into urine and feces, mostly in the form of metabolites. In bile duct-cannulated rats, biliary excretion of radioactivity amounted to about 52% within 24 hr of an orally administered 50 mg/kg dose, with the remainder of the dose being eliminated into urine. The major urinary metabolites resulted from acetylation of the aniline moiety, hydroxylation of the glutarimide ring at positions 3 and 4, and oxidative elimination of the ethyl sidechain. The polar metabolites are accounted for by aromatic hydroxylation with subsequent sulfate conjugation and by a glutarimide ring-opened compound. In addition, a gamma-butyrolactone derivative was also identified.

Diazepam: in vitro effects on glucagon and insulin release.

Diazepam suppressed arginine-induced glucagon release from the isolated perfused rat pancreas in a dose-dependent manner, with an IC50 of approximately 65 microM. In contrast, insulin release was enhanced by 10-50 microM diazepam, but inhibited by higher concentrations of drug. Thus, 50 microM diazepam simultaneously suppressed glucagon and increased insulin release in this model. The potentiation of insulin release may result from phosphodiesterase inhibition. The inhibitory effects on hormone release are discussed in terms of diazepam's molecular conformation, which is similar to that of diphenylhydantoin, an inhibitor of both glucagon and insulin release in the isolated perfused rat pancreas. The possibility is also considered that the conformation of both compounds might be similar to the apparent active site of the hormone release inhibitor somatostatin.