Pharmacokinetics and biological fate of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate (MET-88), a novel cardioprotective agent, in rats

In this study, we examined the disposition, metabolism, and excretion of a novel cardioprotective agent, 3-(2,2,2-trimethylhydrazinium)propionate dihy drate (MET-88), in rats. The disposition of MET-88 after oral and i.v. admi nistration of 2, 20, and 60 mg/kg indicated that the pharmacokinetics of ME T-88 were nonlinear. The profiles of radioactive MET-88 and total radioacti vity in plasma were consistent at doses of 20 and 60 mg/kg. However, at 2 m g/kg, the plasma MET-88 levels were obviously lower than the total. The exc retion of radioactivity after oral administration of MET-88 indicated that increasing doses led to a shift from exhaled CO2 to urinary excretion as th e major excretion route. Major metabolites in plasma after oral administrat ion 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 gamma-butyrobetaine hydroxylase (EC 1.14.11.1). An isolated liver p erfusion system modified to trap CO2 gas was used to examine the excretion pathway of MET-88. [C-14]CO2 gas was decreased by the addition of iodoaceti c acid, DL-fluorocitric acid, or gamma-butyrobetaine to this system, and su bsequent thin-layer chromatography analyses of perfusates revealed that MET -88 was first converted to 3-hydroxypropionic acid by gamma-butyrobetaine h ydroxylase and then was biosynthesized to glucose and metabolized to CO2 ga s via the glycolytic pathway and tricarboxylic acid cycle.