Abstract

In this study, we examined the disposition, metabolism, and excretion of a novel cardioprotective agent, 3-(2,2,2-trimethylhydrazinium)propionate dihydrate (MET-88), in rats. The disposition of MET-88 after oral and i.v. administration of 2, 20, and 60 mg/kg indicated that the pharmacokinetics of MET-88 were nonlinear. The profiles of radioactive MET-88 and total radioactivity in plasma were consistent at doses of 20 and 60 mg/kg. However, at 2 mg/kg, the plasma MET-88 levels were obviously lower than the total. The excretion of radioactivity after oral administration of MET-88 indicated that increasing doses led to a shift from exhaled CO₂ to urinary excretion as the major excretion route. Major metabolites in plasma after oral administration of MET-88 were glucose, succinic acid, and 3-hydroxypropionic acid, and in vitro studies revealed that MET-88 was converted to 3-hydroxypropionic acid by γ-butyrobetaine hydroxylase (EC 1.14.11.1). An isolated liver perfusion system modified to trap CO₂ gas was used to examine the excretion pathway of MET-88. [¹⁴C]CO₂ gas was decreased by the addition of iodoacetic acid, dl-fluorocitric acid, or γ-butyrobetaine to this system, and subsequent thin-layer chromatography analyses of perfusates revealed that MET-88 was first converted to 3-hydroxypropionic acid by γ-butyrobetaine hydroxylase and then was biosynthesized to glucose and metabolized to CO₂ gas via the glycolytic pathway and tricarboxylic acid cycle.