The physiological disposition of ¹⁴C‐methsuximide in the rat

Abstract

Summary1. "C-Methsuximide (N-methyl-"C-2-methyl-2-phenylsuccinimide) was rapidly absorbed from the small intestine of the rat (to 17A4 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 "Cmethsuximide 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 "CO2. The excretion 'of-"CO2 indicated N-demethylation of "C-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.

Studies on the absorption, distribution and elimination of 6-o-chlorophenyl-2,4-dihydro-2(N-methyl-piperazin-1-yl)-methylene-8-nitro-1H-imidazo[1,2-a] [1,4]benzodiazepin-1-one methanesulphonate in the male rat and rabbit

“…The solubilisation of tissues and the determination of radioactivity by scintillation counting was carried out as previously described (5). …”

Pharmacokinetics of Methsuximide and a Major Metabolite in Dogs

“…In rats, it is distributed rapidly into most major tissues and organs (5). Metabolism studies in rats, guinea pigs, dogs, and humans (6)(7)(8) indicate not only that methsuximide is metabolized extensively but also that a prime biotransformation route is N-demethylation, leading to 2-methyl-2-phenylsuccinimide, which is pharmacologically active (2,5,9). There is evidence that this metabolite is cleared slowly from the body relative to the parent drug (10)(11)(12).…”