The physiological disposition of the uricosuric-saluretic agent (6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy)acetic acid (MK-196) in the rat, dog, and monkey

Abstract

The physiological disposition of a new saluretic-uricosuric agent, (6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy)acetic acid (MK-196), was studied in the rat, dog, and monkey. MK-196 was well absorbed and showed minimal metabolism in these species. Peak plasma levels of radioactivity and drug occurred 0.5-2 hr after oral administration at a dose of 2.5 mg/kg. Essentially all of the radioactivity present in the plasma during the first day was intact MK-196. Following a single dose, a long terminal half-life for plasma radioactivity was observed in the dog (approximately 68 hr) and monkey (approximately 105 hr). The chronic administration of MK-196 to dogs resulted in a dose-related plasma profile and showed no tendency to increase or decrease with dosing. However, upon repeated drug administration to monkeys, the plasma levels of drug increased and then decreased, possibly due to hypochloremia and secondary metabolic alkalosis. Fecal excretion was the predominant route of tracer elimination in the dog (approximately 80%) and rat (approximately 94%), whereas the monkey eliminated the majority of the dose (approximately 60%) via the urine. Minimal metabolism was noted in the three lower species; most of the urinary, plasma, and fecal radioactivity was accounted for as intact drug and its glucuronide conjugate. Three minor metabolites, which were present in dog bile, plasma, and urine, were characterized as: (l,7-dichloro-1alpha-hydroxy-2-methyl-2-phenyl-5-indanyloxy)acetic acid, I; (6,7-dichloro-2-(4-hydroxyphenyl)-2-methyl-2-oxo-5-indanyloxy)acetic acid, II; and 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone, III. The monkey urine and plasma also contained small amounts of II.