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 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 CO(2) 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 gamma-butyrobetaine hydroxylase (EC 1.14. 11.1). An isolated liver perfusion system modified to trap CO(2) gas was used to examine the excretion pathway of MET-88. [(14)C]CO(2) gas was decreased by the addition of iodoacetic acid, DL-fluorocitric acid, or gamma-butyrobetaine to this system, and subsequent thin-layer chromatography analyses of perfusates revealed that MET-88 was first converted to 3-hydroxypropionic acid by gamma-butyrobetaine hydroxylase and then was biosynthesized to glucose and metabolized to CO(2) gas via the glycolytic pathway and tricarboxylic acid cycle.
Yoshisue
K
K
Pharmacokinetics Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan. kuni-yosisue@taiho.co.jp
Yamamoto
Y
Y
Yoshida
K
K
Saeki
M
M
Minami
Y
Y
Esumi
Y
Y
Kawaguchi
Y
Y
D000818:Animals; D002250:Carbon Radioisotopes; D002317:Cardiovascular Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008763:Methylhydrazines / Q000378:metabolism / Q000493:pharmacokinetics*; D010477:Perfusion; D020011:Protective Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002250:Carbon Radioisotopes; D002317:Cardiovascular Agents; D008763:Methylhydrazines; D020011:Protective Agents; C050147:3-(2,2,2-trimethylhydrazine)propionate