Metabolism, Blood Levels and Rate of Excretion of Acetohexamide in Human Subjects

Abstract

The metabolism of acetohexamide was studied in normal and diabetic subjects,utilizing acetohexamide-C-14 and hydroxyhexamide-C-14 in two types of experiments. In one, blood levels were determined by an isotopic dilution analysis (IDA). In the other, following the oral and intravenous administration of acetohexamide-C-14, radiocarbon levels in the blood and urine and the nature of the urinary metabolites were elucidated. IDA showed an average half-life for acetohexamide of 1.6 hrs. (range 0.8 to 2.4) and an average half-time for its principal metabolic product, hydroxyhexamide, of 5.3 hrs. (range 3.7 to 6.4). Half-time for total radiocarbon was 5.3 hrs. (range 3.5 to 11). Urinary recovery ofradioactivity after oral doses averaged 71.6 per cent in twenty-four hours. Of the urinary metabolites of acetohexamide (AH) recovered, about 65 per cent was L-hydroxyhexamide (HH) and the remainder consisted chiefly of 4-trans-hydroxyacetohexamide (HAH), 4-trans-hydroxyhydroxyhexamide (HHH), and unchanged acetohexamide with small quantities of other hydroxylated isomers. Fecal excretion was measured in one patient followingthe oral administration and found to be 15 per cent. The observation that, even followingintravenous injection, urinary recovery was only 85 per cent suggested that biliary excretion represents the secondary route of elimination of acetohexamide and/or its metabolites. The radioactivity which was not recovered in the urine at the end of 48 hrs., e.g., on the average 25 per cent, was probably excreted in the stools, resulting from the failure of a small quantity of the tablet to be absorbed and from biliary excretion. The blood and urine data agree with those reported by Sheldon, Anderson and Stoner and confirm the report by Smith, Vecchio and Forist that the half-life of acetohexamide (AH) plus hydroxyhexamide (HH) is comparable to that of tolbutamide. In spite of this relatively short half-life, limited blood sugar data indicate definite hypoglycemic effects up to 24 hrs. after a single 1.0-gm. dose. These findings indicate that the duration of action of AH and its metabolites are not necessarily related to drug levels.