Pharmacokinetics, enterohepatic circulation and biotransformation of [2-3H]-9,9-Dimethylacridane-10-carboxylic acid S-(2-dimethylamino) thiolethyl ester in the rat and dog.
Dogs receiving a 7.5 mg/kg oral or i.v. dose of tritium labelled 9,9-dimethylacridane-10-carboxylic acid S-(2-dimethylamino)thiolethyl ester (DMA) as the methane sulfonate salt (DMA-MS) excreted 86-95% of the radioactivity within 6 days. A similar recovery was obtained for rats receiving 300 mg/kg orally of 15 mg/kg i.v. In both species, approximately 66% of the dose was excreted in the feces as metabolites. Absorption of the oral dose was shown to be 80% and 100% for the rat and dog, respectively. Up to 47% of an i.v. dose was excreted in the bile of rats and an efficient enterohepatic circulation process insues. The parent drug is rapidly metabolized in the tissues yielding at least 6 polar metabolites which contribute to relatively long plasma half-lives in the order of 40 h for dogs and 58-90 h for rats. An atypical increase in plasma radioactivity following an i.v. dose could be rationalized in view of these results. Metabolite profiles were examined in plasma, urine, bile and feces and found to be qualitatively similar. Des-methyl-DMA and DMA-N-oxide were identified as two minor metabolites.
D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002855:Chromatography, Thin Layer; D003124:Colorimetry; D003640:Dealkylation; D004285:Dogs; D004764:Enterohepatic Circulation; D004912:Erythrocytes / Q000378:metabolism; D005243:Feces / Q000032:analysis; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D013045:Species Specificity