Gyula Grézal

Oral, Intraperitoneal and Intravenous Pharmacokinetics of Deramciclane and its N‐desmethyl Metabolite in the Rat

The pharmacokinetic properties of deramciclane fumarate (EGIS‐3886), a new potential anxiolitic agent, and its N‐desmethyl metabolite have been investigated in Wistar rats after 10 mg kg−1 deramciclane fumarate was administered orally, intraperitoneally or intravenously.

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

SummaryThe 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 thespinal 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 (tmax=1.0 h). The concentration-time curves in the tissues can be described by a two compartment open model.The3H-activity could be measured during the whole period of the acute experiment (96 h), whereas14C-radioactivity fell below the detection limit within 24 h. The AUC0−96 values for3H were 10 to 15 times higher than that for14C. In all samples examined, on the concentration time curves a peak characteristic ofenterohepatic 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 the14C-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 of3H-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 for3H were higher than in acute experiments. The last tendency was not observed in the case of14C-tracer. The AUC values of3H-labelled EGIS-3886 determined in subacute experiments predominated over14C; 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.

Studies of the side chain cleavage of deramciclane in rats with radiolabelled compounds

The pharmacokinetics of deramciclane and especially the fate of its side chain were studied in rats after oral treatment, using (3)H- and (14)C-labelled (ring- or side chain labelled) deramciclane and (14)C-dimethylamino-ethanol ((14)C-DMAE) radioisomers. The labelled compounds were admixed and the total radioactivities of both labels were simultaneously determined. The data obtained from the analysis of the plasma concentration-time curves revealed that an intensive cleavage (30-40%) of the side chain occurred at the ether bond. The core of deramciclane, carrying the ring label, was almost completely eliminated during 24 h, while the elimination of the side chain was very slow (t(1/2)(beta): 99 h). The side chain residue most probably represents dimethylamino-ethanol, but the presence of dimethylglycine (DMG) cannot be excluded. The AUC(0-infinity) and the MRT values of DMAE were found to be much higher than those of the parent compound. In addition to the plasma levels, the time related changes of the tissue concentrations of the radioisomers of deramciclane were analysed both in the brain and the hypophysis. The concentration-time curves have shown similar characteristics to those of the plasma, but higher concentrations were reached in both organs (the highest in the hypophysis). It is postulated that the low rate of formation and elimination of the metabolite(s) (DMAE or DMG) indicates that, due to their endogenous nature, they can be incorporated into choline/acetylcholine or protein synthesis.

Comparative bioavailability of alpha-methyldopa normal and film tablet formulations after single oral administration in healthy volunteers.

SummaryIn a single dose, randomized, cross-over study, with one week of wash-out period, the relative bioavailability of Dopegyt® tablets containing 250 mg alpha-methyldopa (AMD) and Presinol® film tablets with identical active ingredient content was examined in 24 healthy volunteers.Since technologically two completely different preparations (a film-tablet and a non-film-tablet) having significantly different in vitro dissolution were to be compared, both preparations were compared to a third one, AMD solution (Dopegyt® solution) with 250 mg/50 ml concentration. Plasma concentrations of the drug were measured for 24 hours post-dose, applying HPLC with fluorometric detection. Pharmacokinetic parameters calculated from individual data (AUC0−∞, AUC0−t, Cmax, Cmax/AUC0−∞, tmax) were evaluated statistically. Wilcoxon’s nonparametric test and the four-way variance analysis could not detect any significant difference at the usual a=95% probability level in these pharmacokinetic parameters of the two tablet preparations. For AUC0−∞ at the 90% probability level, the confidence interval was 0.883–1.237 (with an estimated geometric mean of 1.045), for the test/reference ratio of Dopegyt® and Presinol® tablets, thus the two preparations proved to be bioequivalent. The relative bioavailability of Dopegyt® (test preparation) and Presinol® (reference preparation) calculated from the AUC0−∞ values was 116.7±56.7% that also confirmed bioequivalence. The results of all the applied statistical tests suggest that Dopegyt® and Presinol® can be considered as bioequivalent preparations.

Comparative bioavailability of two different rectal preparations of piroxicam in man

SummaryA comparative pharmacokinetic study was performed with two types of suppository each containing 20 mg piroxicam. The bioavailability of piroxicam was studied in 24 healthy volunteers in a double blind, randomised, cross over study.No significant difference was found in the pharmacokinetic parameters [AUC(0–72 h), AUC, Cmax, t1/2β calculated from plasma concentration time curves, indicating that the two preparations were bioequivalent.