DISTRIBUTION OF DERAMCICLANE (EGIS-3886) IN RAT-BRAIN REGIONS

The time related distribution and pharmacokinetics of double-labelled EGIS-3886 (EGIS-3886-phenyl-C-14 and -ethyl-H-3) were studied in the p lasma, hypophysis and 14 cerebral regions, including the spinal cord o f the rat after a single oral treatment (acute experiments) and after repeated administration of one dose daily for six days (subacute exper iments). The tissue levels of EGIS-3886 (deramciclane) were calculated from the simultaneously determined dpm values and the specific activi ties of the two radioisomers present in the dose administered. EGIS-38 85 was rapidly absorbed from the gastrointestinal tract t(max)=1.0 h). The concentration-time curves in the tissues can be described by a tw o compartment open model. The H-3-activity could be measured during th e whole period of the acute experiment (95 h), whereas C-14-radioactiv ity fell below the detection limit within 24 h. The AUC(0.96) values f or H-3 were 10 to 15 times higher than that for C-14. I, all samples e xamined, on the concentration time curves a peak characteristic of ent erohepatic cycle can be seen at 12 h. The studies indicated that intac t molecules entered brain tissues from the circulation. The results of the subacute experiments indicate that the C-14-labelled EGIS-3886, o r its metabolite(s) carrying the tracer, reach an equilibrium as early as on the second to third day, whilst the level of H-3-radioactivity continually increases during the six days of repeated administration. In the subacute experiments the peak concentrations were reached at 0. 5 h after the final treatment. However, their values for 3H were highe r than in acute experiments. The last tendency was not observed in the case of C-14-tracer. The AUC values of H-3-labelled EGIS-3886 determi ned in subacute experiments predominated over C-14; the ratios were 50 to 60 in all brain regions. The enterohepatic cycle, seen after a sin gle dose, also operated after repeated dosage. The time related concen trations of EGIS-3886 in the hypophysis were at least two times higher than that in the plasma and the brain tissues. No significant differe nce was seen in the concentrations of EGIS-3886 in the symmetrical (le ft and right) regions of the brain.