RELATIONSHIP BETWEEN DURATION OF ANTICONVULSANT ACTIVITY OF CHLORIDIAZEPOXIDE AND SYSTEMIC LEVELS OF PARENT COMPOUND AND ITS MAJOR METABOLITES IN MICE

The duration of the anticonvulsant (antimetrazol) activity of chlordiazepoxide in mice in relation to blood levels and tissue distribution patterns of the parent drug and its major metabolites is presented. Quantitation of the effect of a 125 mg/kg s.c. injection of metrazol and the degree of protection by a single 20 mg/kg oral dose of chlordiazepoxide, based on measuring the incidence of defined seizure reactions, indicated maximal protection for 4 hr after chlordiazepoxide administration. The quantitative 14C distribution after the oral administration of a single 20 mg/kg dose of chlordiazepoxide-2-14C is indicative of a rapid absorption onset as well as of a gradual increase in the tissue-to-blood 14C ratios from 0.5 to 6 hr after administration. In contrast, a 125 mg/kg subcutaneous injection of metrazol given 30 min after the oral administration of chlordiazepoxide appears both to reduce markedly the rate of absorption and to alter the disposition of chlordiazepoxide. This alteration includes a reduction in the blood 14C and tissue 14C levels immediately after metrazol injection to 4 hr after chlordiazepoxide administration. Although the initial tissue-to-blood 14C ratios are similar to those seen in the absence of metrazol, they do not show the marked increment with time. Differential spectrofluorometric analyses of blood, brain and muscle tissue samples for chlordiazepoxide and its major metabolites show that N-desmethylchlordiazepoxide is the major constituent in all three tissues both in the absence and in the presence of metrazol. Besides being present in much higher concentrations, unlike the parent compound and other metabolites, the N-desmethyl derivative maintains a maximum level from 30 min to 4 hr in the brain and from 30 min to 6 hr in blood and muscle. Correlation of the levels of chlordiazepoxide and its metabolites in these tissues to its anticonvulsant (antimetrazol) activity indicates that it is the concentration of the N-desmethyl metabolite that most closely parallels the pattern of this anticonvulsant activity. © 1969.