BIOTRANSFORMATION OF THE NOVEL INOTROPIC AGENT TOBORINONE (OPC-18790)IN RATS AND DOGS - EVIDENCE FOR THE FORMATION OF NOVEL GLUTATHIONE AND 2 CYSTEINE CONJUGATES

The metabolism of toborinone, xybenzylamino)-2-hydroxypropoxy]-2(1H)-q uinolinone 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 [C-14]toborinone, fecal and urinary recoveries of the C-14 dose were similar to 70% and 25-30%, respectively, in both rats and dogs. T he predominant component of radioactivity was the unchanged toborinone in every biological specimen in rats and dogs, Although unchanged tob orinone was predominantly observed, toborinone underwent extensive con jugations with glucuronic acid, sulfate, and glutathione, either direc tly or following phase I reaction. Metabolites resulting from oxidativ e N-C cleavage were minor both in number and in quantity in every biol ogical specimen in rats and dogs, In rats, toborinone underwent O-deme thylation to form M-7 and successive phase II reaction to yield the gl ucuronide M-1 and the sulfoconjugate M-2, and deconjugation to yield M -7, which was a primary metabolite accounted for 35.67% of the radioac tivity 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, cystein e 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 sp ecies 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 we re minor in quantity, The metabolic pathways of toborinone in rats and dogs are proposed herein.