METABOLISM OF DIAZOXIDE IN MAN AND EXPERIMENTAL ANIMALS

¹ Departments of Pediatrics, Medicine and Pharmacology and the Clinical Pharmacology Program, Emory University School of Medicine, Atlanta, Georgia

After diazoxide(3-¹⁴C) was synthesized, the fate of the drug in human, monkey, dog, rabbit, guinea pig and rat was investigated. The half-life of the drug in plasma varied from 1 to 2 hours in the rabbit to 17 to 29 hours in monkey and man. In man, monkey and dog, two metabolites of ¹⁴C-diazoxide were identified: 3-hydroxymethyl-7-chloro-1,2,4-benzothiadiazine-1,1-dioxide (M-1) and 3-carboxy-7-chloro-1,2,4-benzothiadiazine-1,1-dioxide (M-2). In those species, the metabolites were present in plasma in low concentration. However in two human volunteers, M-1 and M-2 accounted for 21 and 23% of the radioactivity in urine, respectively, and 31% of the ¹⁴C in urine was unchanged drug. In monkey, diazoxide, M-1 and M-2 accounted for 70, 13 and 10% of the radioactivity, respectively, in urine. The presence of M-1 and M-2 in urine was also demonstrated in the dog after oral and intravenous administration of ¹⁴C-diazoxide. In contrast, there was no appreciable metabolism of the drug in rabbit, guinea pig and rat. Therefore, the monkey and dog appear to be the best experimental species for use in further study of the disposition of this drug.