Metabolism of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (M73101), a new anti-inflammatory agent. II. Species differences of metabolism and excretion.

Abstract

The species differences of metabolism of 4-ethoxy-2-methyl-5-morpholino-3 (2H)-pyridazinone (M73101) were studied. The urinary and fecal metabolites in six animals (dog, mouse, rabbit, rat, monkey, and guinea pig) were analyzed qualitatively and quantitatively by thin-layer chromatography and gas-liquid chromatography in addition to gas chromatography-mass spectrum determination. From the results of qualitative analysis, seven to ten metabolites in urine were identified in each animal. From the results of quantitative analysis, total excretion percentage of unchanged M73101 and its metabolites in urine were 50.0, 48.4, 73.8, 56.1, 52.7, and 21.1% of the dose administered in dogs, mice, rabbits, rats, monkeys, and guinea pigs, respectively. The main metabolite excreted in urine was 5-[2-(carboxymethyloxy) ethylamino]-4-ethoxy-2-methyl-3 (2H)-pyridazinone (M-9) in dogs, mice, rabbits, and rats and 5-(N-carboxymethyl-N-2-hydroxy-ethylamino)-4-ethoxy-2-methyl-3 (2H)-pyridazinone (M-8) in monkeys and guinea pigs. For the fecal excretion, 59.4, 19.5, 17.7, and 15.3% of the dose administered were excreted in guinea pigs, mice, dogs, and rats, respectively, and rabbits and monkeys hardly excreted any metabolites. From the results of urinary and fecal excretion, the main excretion route was through liver and bile duct into feces in guinea pigs and was into urine in other five animals. For the effects of the dose administered on metabolism, dose-dependent variations of metabolism characteristic of guinea pigs were observed in biliary excretion, that is, main metabolite was M-8 in low dose (20mg/kg) while M-9 in high dose (500mg/kg) but such phenomenon was not found in rats.