THE BIOTRANSFORMATION OF PROTRIPTYLINE IN MAN, PIG AND DOG

¹ Research Division, Wyeth Laboratories, Inc., Radnor, Pennsylvania

An investigation into the metabolic fate of protriptyline (I) has revealed an oxidative metabolic transformation occurring in dog, miniature swine and man which leads to three urinary metabolites, namely, 10-hydroxy-N-methyl-5H-dibenzo[a,d]cyclohepteue-5-propylamine (II), 10,11-dihydroxy-N-methyl-5H-dibenzo[a,d] cycloheptane-5-propylamine (III) and 5,10-dihydro-10-formylanthracene-5-propylamine (IV). Metabolites II and III also appear as glucuronides. A fourth urinary metabolite, the primary amine resulting from N-demethylation of the drug, appears only in the dog. Furthermore, unchanged drug also is found in the urine of each species. The confirmation of the appearance of unchanged drug in urine and the identification of the metabolites was made with analytical and preparative thin-layer and gas-liquid chromatography as well as mass spectrometry. No qualitative change in the metabolite picture was observed between human subjects given a single dose and those dosed chronically for two weeks. Similarly, prolonged dosing in the two animal species did not result in a change of the metabolic pattern. Tissue extracts from dog and miniature swine also were found to contain the same metabolites as were found in the urine of the respective species.