Metabolism of a new positive inotropic agent, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)- quinolinone (OPC-8212) in the rat, mouse, dog, monkey and human.
1. After OPC-8212 was orally given to rats, mice, dogs, monkeys and humans, its metabolites were identified by n.m.r. and mass spectrometry, and their concentrations in the plasma, urine and faeces of these species were measured by high-performance liquid chromatography (h.p.l.c.). 2. Hydrolysis of the amide group, oxidation and cleavage of the piperazine ring, O-demethylation of the methoxy group, and conjugation were proposed as metabolic pathways of OPC-8212. 3. In rats, mice and monkeys given OPC-8212 orally, metabolites M-1 to M-6 were detected in the plasma, urine and faeces, while M-1, -4, -5 and M-6 were detected in dogs, and M-1, M-3, M-4, M-5 and M-6 were detected in humans. 4. Conjugates of metabolites M-6 and M-7, with glucuronic acid and sulphuric acid, were observed in the urine of rats and humans.
Miyamoto
G
G
Laboratory of Drug Metabolism, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Japan.
Sasabe
H
H
Tominaga
N
N
Uegaki
N
N
Tominaga
M
M
Shimizu
T
T
D000328:Adult; D000818:Animals; D002316:Cardiotonic Agents; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011719:Pyrazines; D011804:Quinolines / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
D002316:Cardiotonic Agents; D011719:Pyrazines; D011804:Quinolines; C041667:vesnarinone