THE DETERMINATION AND PHYSIOLOGICAL DISPOSITION OF MILONTIN (N-METHYL--PHENYLSUCCINIMIDE)

¹ Research Laboratories, Parke, Davis and Company, Detroit, Michigan

1. A sensitive analytical method is described for the determination of Milontin in biological materials. This is based on a reaction of Milontin with iodine, producing a fluorescent product which has been isolated and identified as N-methyl--phenylmaleimide.

2. Blood level studies in man indicate that maximum levels are attained in 1-2 hours after a single oral dose, dropping to low levels in 8-12 hours and to zero after 24 hours. The blood level-time curve in patients receiving Milontin for long periods of time was about the same as observed in subjects receiving the drug for the first time.

3. The tissue distribution of Milontin was studied in rats following oral administration of radioactive C-14 labelled Milontin. The concentration in different tissues was fairly uniform, with Milontin concentrations in the brain tissue being about the same as in blood serum. The proportion of metabolites to free Milontin in different tissues was found to increase with time.

4. Using single oral doses of radioactive Milontin, urinary excretion in rats was found to account for approximately two-thirds of the dose in 24 hours, with appreciable quantities appearing in the urine in the 24-48 hour period. Only traces of free Milontin were detected in rat urine by the fluorimetric method.

5. The metabolites of Milontin in rat urine were examined by paper chromatography, and partly characterized. The principal metabolites appear to be hydrolysis products of Milontin, in which the succinimide ring is opened. Human urine was found to contain two metabolites of Milontin which form red-colored derivatives upon treatment with iodine. A similar color reaction was obtained with N-methyl--(p-hydroxyphenyl) succinimide.