Abstract

As part of a program to investigate the metabolism and disposition of putative dopamine receptor agonists, DK-118 (5-hydroxy-6-methyl-2-di-n-propylaminotetralin) was chosen for study in the rat. Following a 3.85 mg/kg (ip) dose of 5-hydroxy[6-14C]methyl-2-di-n-propylaminotetralin, an average (+/- SD) of 100.3 +/- 12.2% was recovered in 67 hr: 77.2 +/- 7.9% in urine and 23.1 +/- 6.2% in feces. No excretion of 14CO2 was observed. In bile duct-cannulated animals, an average of 31.6% of the dose was recovered in the bile within 6 hr. After injection of bile containing radiolabeled drug/metabolites into the lumen of the duodenum, 30.2 +/- 1.7% of the injected radioactivity was recovered in the urine, suggesting enterohepatic circulation of some of the drug/metabolites excreted in bile. Highest concentrations of tissue radioactivity, 0.5 hr after ip injection of 14C-DK-118, were found in lung, kidney, and liver. Only a small amount of unchanged DK-118 is excreted into urine and bile; HPLC radiochromatography separated five metabolites in urine and at least eight metabolites in bile. The three major metabolites in urine (70% of urinary radioactivity) have been identified as 5-hydroxy-6-carboxy-2-di-n-propylaminotetralin, 5-hydroxy-6-carboxy-2-n-propylaminotetralin, and 5-hydroxy-6-methyl-2-n-propylaminotetralin-O-sulfate. The two major biliary metabolites have been identified as 5-hydroxy-6-carboxy-2-n-propylaminotetralin and an acid-labile conjugate of DK-118. Together, these data indicate that DK-118 is metabolized in the rat by a combination of N-dealkylation, oxidation of the 6-methyl carbon, and conjugation with sulfate.