The physiological disposition of 14C‐methsuximide in the rat

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Abstract
1 . 14C-Methsuximide (N-methyl-14C-2-methyl-2-phenylsuccinimide) was rapidly absorbed from the small intestine of the rat (t½ 17·4 min). 2 . The drug was rapidly and fairly evenly distributed throughout the body with peak blood and tissue levels occurring 1 h after oral administration. At all times, adrenals, body fat, kidneys and liver had higher levels of 14C-methsuximide than other tissues and the drug freely traversed the blood-brain barrier. However, radioactivity disappeared rapidly from most tissues after the initial phase of the distribution. 3 . During 24 h, 26% of the orally administered radioactivity was recovered in urine and 29% appeared in expired air as 14CO2. The excretion of 14CO2 indicated N-demethylation of 14C-methsuximide to 2-methyl-2-phenylsuccinimide. 2·7% of an administered dose of methsuximide was excreted unchanged in 24 h urine and 2·7% appeared as 2-methyl-2-phenylsuccinimide. 2-Methyl-2-phenylsuccinimide was also detected as a urinary metabolite of methsuximide in man. 4 . 2-Methyl-2-phenylsuccinimide possesses anticonvulsant activity and it is suggested that this metabolite contributes to the overall anticonvulsant activity and toxicity of methsuximide. 5 . Rat urine also contained a radioactive substance with similar chromatographic properties to one of the products of alkaline hydrolysis of methsuximide. This compound may arise from the spontaneous decomposition of the parent drug in vivo.