Biotransformation of benzamidine and benzamidoxime in vivo

After administration of benzamidine (1) or benzamidoxime (2), respectively, to rats and rabbits, plasma from rats and rabbits as well as urine from rats were examined for the presence of benzamidoxime (2) or benzamidine (1). Some of the samples were worked-up directly and the others after enzymatic pretreatment with beta-glucuronidase or arylsulfatase, respectively. HPLC analysis was employed for the detection of the metabolites. After administration of 1, an in vivo N-hydroxylation of an amidine to an amidoxime was demonstrated for the first time. The metabolite 2 could only be detected after enzymatic cleavage of the glucuronide or sulfate, respectively, and only in plasma at a low concentration. After administration of benzamidoxime (2), on the other hand, benzamidine (1) was detected in very high concentrations in all biological samples. Benzamidine was present in the free state but indications for glucuronidization and sulfatation were also detectable. These investigations suggest that the benzamidoxime (2) formed by an in vivo N-hydroxylation undergoes ready retro-reduction but that further transformations of the metabolite 2, such as conjugation to a glucuronide or a sulfate, respectively, prevent complete back reaction. Furthermore, benzamide (3) could be detected as a transformation product in urine after administration of either 1 or 2.