THE NATURE OF THE METABOLITES OF ACETOHEXAMIDE IN THE RAT AND IN THE HUMAN

¹ Lilly Research Laboratories, Indianapolis, Indiana

Evidence is presented which indicates that the hydroxyhexamide which Welles et a1. (1961) have shown to be the major metabolite of acetohexamide in humans has the L-configuration.

L(-)-Hydroxyhexamide is an effective hypoglycemic agent and is thought to contribute significantly to the hypoglycemic response which follows administration of acetohexamide.

A second route of metabolism in the human, rat, and mouse was found to be hydroxylation of the cyclohexane ring. Hydroxylated metabolites appear in urine in both the hydroxy-acetohexamide form and the hydroxyhydroxy-hexamide form. Each species produces a mixture of isomers with respect to the position of hydroxylation of the cyclohexyl ring. Thus, in the human and mouse the 4'-trans-hydroxy isomer predominates while in the rat 3'- trans-hydroxy is dominant. 4'-Trans-hydroxyacetohexamide was found to possess some hypoglycemic activity while the reduced form (±)-4'-trans-hydroxyhydroxyliexamide does not.

The rate of reduction of acetohexamide in the rat is not increased by chronic feeding of either phenobarbital or acetohexamide. Chronic administration of phenobarbital, but not acetohexamide, causes some increase in the rate of hydroxylation.

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