Gas-chromatographic simultaneous analysis for glutethimide and an active hydroxylated metabolite in tissues, plasma, and urine.

We report a gas-chromatographic method for the simultaneous quantitative analysis of both glutethim-ide and 4-hydroxy-2-ethyl-2-phenylglutarimide (4-HG), an active metabolite of glutethimide, in tissues, plasma, and urine. The method, applied to postmor-tem tissues from cases of fatal glutethimide over-dose and to plasma samples obtained from a patient in coma from acute glutethimide intoxication, proved to be accurate, sensitive, and specific. Results of the analysis confirm that 4-HG accumulates in plasma and tissues during glutethimide intoxication. Because 4-HG has been shown previously to be at least as potent as glutethimide itself, its accumulation may play an important role in the acute toxicity of glu-tethimide. Glutethimide, 2-ethyl-2-phenylglutarimide, is a sedative-hypnotic similar in structure and biological activity to the barbiturates. Although early reports claimed that glutethimide was relatively free from the adverse effects often associated with acute over-doses of the barbiturate drugs (1), many cases of se-rious intoxication with glutethimide were subse-quently reported (2-12). The management of glu-tethimide poisoning is now clearly established as a serious clinical problem (13-17). Ambre and Fischer have recently reported that 4-HG,1 a metabolite of glutethimide (Figure 1), accu-mulated to concentrations much higher than the concentrations of unchanged drug in the plasma of humans intoxicated by glutethimide overdose (18, 19). The metabolite was subsequently isolated and purified from the urine of dogs given large doses of glutethimide. This biosynthetically prepared 4-HG possessed sedative-hypnotic activity in mice that was equal to or greater than that of glutethimide it-self (19). Thus, it is quite likely that 4-HG could play an important role in the etiology of glutethim-ide intoxication.