Studies on the Mechanism of the Epileptiform Activity Induced by U18666A. II. Concentration, Half‐Life and Distribution of Radiolabeled U18666A in the Brain

Abstract

The concentration, half-life and distribution in brain of U18666A [3-.beta.-(2-diethylaminoethoxy)-androst-5-en-17-one HCl], a drug that can drastically alter cerebral lipids and induce a chronic epileptiform state, was determined following both acute and chronic drug administration in rats. U18666A specifically labeled with tritium was prepared by custom synthesis. Brain levels of 1 .times. 10-6 M and higher were reached soon after giving an acute 10-mg/kg dose (i.p. or s.c.) of U18666A containing 7-3H-U18666A of known specific activity. A steady state concentration of 1-2 .times. 10-6 M was reached with chronic injection of 10 mg/kg every 4th day, a treatment schedule that results in altered brain lipids and induction of epilepsy if begun soon after birth. The disappearance of U18666A from both brain and serum was described by 2 similar biexponential processes, a brief rapid clearance (t1/2 = 10 h) and a sustained and much slower one (t1/2 = 65 h). Brain levels of the drug were .apprx. 10 times higher than serum examined at all times. Few differences were seen in the regional distribution of radiolabeled drug in brain as determined by both direct analyisis and by autoradiographic examination; the drug did concentrate in lipid-rich subcellular fractions. For example, the synaptosome and myelin fractions each contained .apprx. 25-35% of both the total 3H-labeled drug and total lipid in whole brain. The lipid composition of these fractions was drastically altered in treated animals. The chronic epileptiform state induced by U18666A does not appear to involve localization of the drug in a specific brain region or particular cell type. Rather, the condition could involve localization of the drug in lipid-rich membranes and marked changes in the composition of these membranes.