Hypoglycemic effect of S(−)-hydroxyhexamide, a major metabolite of acetohexamide, and its enantiomer R(+)-hydroxyhexamide

A short-lasting hypoglycemic effect was observed when S(−)-hydroxyhexamide ( S-HH), a major metabolite of acetohexamide, and its enantiomer R(+)-hydroxyhexamide ( R-HH), were administered orally to rats. Since the reductive metabolism of acetohexamide is known to be reversible in rats, oral administration of R-HH may exhibit the hypoglycemic effect through the generation of acetohexamide. However, oral administration of R-HH to rabbits, in spite of their inability to oxidize R-HH to acetohexamide, caused a significant decrease and increase, respectively, of plasma glucose and insulin levels. Furthermore, both S-HH and R-HH were found to stimulate the secretion of insulin from hamster HIT T15 cells (pancreatic β-cells). These results provide further evidence that both R-HH and S-HH exhibit a significant hypoglycemic effect.