Distribution of deramciclane (EGIS-3886) in rat brain regions

Abstract

The time related distribution and pharmacokinetics of double-labelled EGIS-3886 (EGIS-3886-phenyl-14C and -ethyl-3H) were studied in the plasma, hypophysis and 14 cerebral regions, including the spinal cord of the rat after a single oral treatment (acute experiments) and after repeated administration of one dose daily for six days (subacute experiments). The tissue levels of EGIS-3886 (deramciclane) were calculated from the simultaneously determined dpm values and the specific activities of the two radioisomers present in the dose administered. EGIS-3886 was rapidly absorbed from the gastrointestinal tract (t(max)=1.0 h). The concentration-time curves in the tissues can be described by a two compartment open model. The 3H-activity could be measured during the whole period of the acute experiment (96 h), whereas 14C-radioactivity fell below the detection limit within 24 h. The AUC(0-96) values for 3H were 10 to 15 times higher than that for 14C. In all samples examined, on the concentration time curves a peak characteristic of enterohepatic cycle can be seen at 12 h. The studies indicated that intact molecules entered brain tissues from the circulation. The results of the subacute experiments indicate that the 14C-labelled EGIS-3886, or its metabolite(s) carrying the tracer, reach an equilibrium as early as on the second to third day, whilst the level of 3H-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 higher than in acute experiments. The last tendency was not observed in the case of 14C-tracer. The AUC values of 3H-labelled EGIS-3886 determined in subacute experiments predominated over 14C; the ratios were 50 to 60 in all brain regions. The enterohepatic cycle, seen after a single dose, also operated after repeated dosage. The time related concentrations of EGIS-3886 in the hypophysis were at least two times higher than that in the plasma and the brain tissues. No significant difference was seen in the concentrations of EGIS-3886 in the symmetrical (left and right) regions of the brain.

Comparative studies of the in vitro dissolution and in vivo pharmacokinetics for different formulation strategies (solid dispersion, micronization, and nanocrystals) for poorly water-soluble drugs: A case study for lacidipine

“…In this study, all three test formulations all exhibited both a peak and a hump. It usually indicated the enterohepatic cycle was involved in oral absorption [23]. However, literatures about the enterohepatic cycling of LCD were not available after investigation.…”

Synthesis of deramciclane* labeled with tritium in various positions

“…[5][6][7][8][9][10] The resulting metabolite and derivatives show increased distribution and significant plasma levels for a longer biological half-life than the parent compound. 11,12 Two tritium labelled forms of deramciclane were required with the label in the camphor skeleton, ( [3-3 H]deramciclane (3)) and the side chain ([2-dimethylamino- [2][3] H]ethoxy]deramciclane (9)) for in vitro and in vivo studies to further investigate various aspects of the metabolism and pharmacokinetics of deramciclane. [11][12][13][14][15][16][17][18][19] Previous studies with 3 H and 14 C labelled deramciclane had showed that the metabolism of the camphor skeleton and side chain could be differentiated by virtue of their significantly different biological half-life values.…”