BIOTRANSFORMATION OF DIPHENOXYLATE IN RAT AND DOG

¹ Division of Biochemical Research, G. D. Searle & Company, Chicago, Illinois

The biotransformation of ¹⁴C-diphenoxylate hydrochloride was studied in the rat and dog. In both species only a small fraction (\<7%) of the administered label appeared in the urine. The major portion of the label (\>60%) was recovered in the feces. In one dog in which the drug was first administered p.o. and then i.v. no significant difference was found in the proportion of the label detected in the urine and feces. The importance of biliary excretion of diphenoxylate and its metabolites was indicated in a bile-cannulated rat in which 90% of the administered label was recovered in the bile. From fecal samples, five metabolites were isolated and their structures elucidated by thin-layer and gas-liquid chromatographic studies and by detailed spectroscopic analysis. In the rat the de-esterifled compounds diphenoxylic acid and its phenolic analog were the major metabolites, whereas in the dog, besides the diphenoxylic acid, a large amount of phenol, a methoxyphenol and a dihydrodiol analog of diphenoxylate were also present.

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