Biotransformation of the novel inotropic agent toborinone (OPC-18790) in rats and dogs. Evidence for the formation of novel glutathione and two cysteine conjugates.
The metabolism of toborinone, (+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-quin - olinone, a novel inotropic agent, was studied in rats and dogs after intravenous administration. Chemical structures of the 13 metabolites were characterized by direct-probe FAB/MS and field desorption/MS, LC/FAB/MS, and various NMR measurements. After intravenous dosing of 10 mg/kg [14C]toborinone, fecal and urinary recoveries of the 14C dose were approximately 70% and 26-30%, respectively, in both rats and dogs. The predominant component of radioactivity was the unchanged toborinone in every biological specimen in rats and dogs. Although unchanged toborinone was predominantly observed, toborinone underwent extensive conjugations with glucuronic acid, sulfate, and glutathione, either directly or following phase I reaction. Metabolites resulting from oxidative N-C cleavage were minor both in number and in quantity in every biological specimen in rats and dogs. In rats, toborinone underwent O-demethylation to form M-7 and successive phase it reaction to yield the glucuronide M-1 and the sulfoconjugate M-2, and deconjugation to yield M-7, which was a primary metabolite accounted for 35.67% of the radioactivity excreted in the feces by 48 hr. Conjugates M-1 and M-2 were the major metabolites in rat plasma. In dogs, toborinone was metabolized via mercapturic acid pathway to yield the primary metabolites, cysteine conjugates M-10 and M-11 that accounted for 19.10% and 6.70% of the radioactivity excreted in the feces by 48 hr and that were detected species specifically in dogs. The glutathione conjugate M-13, which was isolated from in vitro incubations using dog liver, led us to consider a possible mercapturic acid pathway from the parent compound to M-10. Metabolites in dog plasma and those in urine in both rats and dogs were minor in quantity. The metabolic pathways of toborinone in rats and dogs are proposed herein.
Kitani
M
M
Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Japan.
Miyamoto
G
G
Nagasawa
M
M
Yamada
T
T
Matsubara
J
J
Uchida
M
M
Odomi
M
M
D000818:Animals; D001711:Biotransformation; D002316:Cardiotonic Agents / Q000097:blood / Q000378:metabolism* / Q000652:urine; D003545:Cysteine / Q000097:blood / Q000652:urine; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005978:Glutathione / Q000097:blood / Q000652:urine; D008297:Male; D013058:Mass Spectrometry; D015363:Quinolones / Q000097:blood / Q000378:metabolism* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000097:blood / Q000378:metabolism* / Q000652:urine
D002316:Cardiotonic Agents; D015363:Quinolones; D014665:Vasodilator Agents; C077543:toborinone; D005978:Glutathione; D003545:Cysteine