The biotransformation of (6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy) acetic acid (MK-196) in the chimpanzee.
The metabolism of a novel polyvalent saluretic agent (6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy)acetic acid (MK-196) was studied in the chimpanzee. Following oral administration, 50% of the radioactive dose was recovered in the urine in four days; 8-14% of the dose was excreted as unchanged drug. The fecal specimens accounted for 5-9% of the dose. Following intravenous administration an initial rapid elimination of drug from the plasma was observed [(t1/2)alpha approximately 0.4 hr, (t1/2)beta approximately 4 hr]. The data are consistent with the rapid elimination of radioactivity, approximately 30% of dose, in the urine during the first 24 hr, followed by a much slower rate of excretion of drug and metabolites. These findings are congruous with the high affinity (greater than 98%) of MK-196 and the major metabolite with plasma proteins. The urinary metabolites were isolated and identified by the following techniques: solvent extraction, column, thin-layer, and gas-liquid chromatography, derivatization, and mass and nuclear magnetic resonance spectroscopy. The major metabolite, which resulted from para-hydroxylation of the 2-phenyl substitutent, accounted for about 40% of the urinary radioactivity. Reduction of the ketone group, methylation of the p-hydroxy group, and additional phenyl ring hydroxylation were also shown to occur. There was no evidence for glucuronide formation nor did SKF-525-A inhibit the metabolism of the drug in the chimpanzee. Under conditions of induced metabolic alkalosis, the urinary levels of MK-196 increased from 11 to 40%. Probenecid and p-aminohippurate administered during metabolic alkalosis decreased the clearance of drug (40 to 15%).
D000284:Administration, Oral; D000818:Animals; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002849:Chromatography, Gas; D002855:Chromatography, Thin Layer; D004232:Diuretics / Q000008:administration & dosage / Q000378:metabolism*; D007189:Indans / Q000008:administration & dosage / Q000378:metabolism*; D007192:Indenes / Q000378:metabolism*; D007263:Infusions, Parenteral; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D002679:Pan troglodytes; D011335:Proadifen / Q000494:pharmacology; D011485:Protein Binding
D001798:Blood Proteins; D004232:Diuretics; D007189:Indans; D007192:Indenes; D011335:Proadifen