MECHANISM OF THE FORMATION IN-VIVO OF ALPHA-PHENYL-GAMMA-LACTONES IN THE GLUTETHIMIDE SERIES

The isolation of gamma-lactones from the urines of humans or animals t reated with glutethimide or aminoglutethimide required an explanation. The question was studied on the glutethimide model. Potential metabol ites such as beta-hydroxymetabolite, gamma-lactone amide, and gamma-la ctone acid were synthesized. Glutethimide was first administered to ra ts at high and normal doses. The corresponding gamma-lactone amide, re sulting from alcoholysis of beta-hydroxyglutethimide, was also adminis tered to rats. The amounts of the various gamma-lactone derivatives is olated from the urine were discussed and it was concluded that the alp ha-phenyl-gamma-lactone was formed in vivo via beta-hydroxylation of g lutethimide followed by intramolecular alcoholysis. The lactone amide was then oxidized and dealkylated via an intramolecular mechanism lead ing to the corresponding alpha-phenyl-gamma-lactone.