Capillary gas chromatographic method for determination of flumecinol in plasma and saliva.
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Animals↗
Biomedical subjects
I Klebovich
Publications and source records attributed to I Klebovich.
Pharmacokinetic studies of flumecinol in man and dog.
The pharmacokinetics of flumecinol (Zixoryn) a new hepatic enzyme inducer has been studied in four beagle dogs and six healthy volunteers. The beagle dogs and the volunteers received the drug orally in a dose of 40 mg/kg of body weight and of 100 mg single dose respectively. Flumecinol was extracted from plasma with diethyl ether and analysed by gas-liquid chromatography using a flame ionisation detector (FID). The pharmacokinetic parameters of flumecinol were determined by computer evaluation of the plasma concentration-time curves. The peak plasma concentrations were found to be 5.3 and 2.1 hours in dogs and humans, respectively. Flumecinol is eliminated from the plasma of dogs and humans with half-lives of 38.95 and 17.16 hours, corresponding to a clearance of 53.2 litres/hour and 94.0 litres/hour, respectively.
Adult↗
Gas chromatographic method for the determination of flumecinol in biological fluids.
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Animals↗
Comparative bioavailability studies on two oral diazepam preparations.
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Biological Availability↗
Distribution of deramciclane (EGIS-3886) in rat brain regions.
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.
Animals↗
Comparative bioavailability of alpha-methyldopa normal and film tablet formulations after single oral administration in healthy volunteers.
In 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-infinity, AUC0-t, Cmax, Cmax/AUC0-infinity, t(max)) 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-infinity 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-infinity 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.
Adrenergic alpha-Agonists↗
Metabolite analysis, isolation and purity assessment using various liquid chromatographic techniques combined with radioactivity detection.
During the discovery of metabolic routes of a drug candidate, radioactively labeled substances are administered. This study reports the multidimensional application of overpressured layer chromatography (OPLC) and high-performance liquid chromatography (HPLC) coupled with online or off-line nondestructive radioactivity detection methods in metabolism studies. Among these methods, digital autoradiography and flow-cell radioactivity detectors (RD) using solid scintillators are used. In this study, the hyphenation of OPLC with RD is reported. The application of the OPLC-RD technique is demonstrated on a metabolism study as well as the multidimensional chromatographic selectivity using normal-phase OPLC for the separation in the first dimension, followed by reversed-phase HPLC-RD, which provides additional selectivity to the separation. Information regarding the identity of radiolabeled metabolites and data obtained from spectroscopic methods could be advantageously used during structure elucidation.
Chromatography, High Pressure Liquid↗
Application of overpressured layer chromatography combined with digital autoradiography and mass spectrometry in the study of deramciclane metabolism.
Overpressured layer chromatography was combined with the highly sensitive and rapid digital autoradiography (DAR) and mass spectrometry to separate, detect, and identify 3H- and 14C-labeled deramciclane metabolites in different biological matrixes. Several minor and major metabolites were separated from plasma and urine samples. The radioactive metabolites localized by DAR were scraped from the thin-layer chromatographic plate and transferred to a mass spectrometer for structure identification. Several metabolites were isolated and characterized, including hydroxy-N-desmethyl deramciclane, which is described in detail. The combination of techniques is efficient and has good sensitivity: about 2 micrograms metabolite from a biological matrix was isolated and identified this way.
Animals↗
[Pharmacokinetic study of nerisopam and its n-acetyl metabolite in rats].
Three doses were administered to the rats during the pharmacokinetic study of nerisopam and the plasma concentrations of nerisopam and its N-acetyl metabolite were determined parallelly by means of validated SPE-HPLC method developed by the authors. The pharmacokinetics of nerisopam could be described by a two-compartment open model in rats, it was absorbed rapidly and could be measured in plasma for about 8 hours. The peak plasma concentration of the N-acetyl metabolite was reached rapidly a little bit later than that of the parent compound, similarly to the human plasma, and it could be measured for about 12 hours. The pharmacokinetics of N-acetyl metabolite could be described by an one-compartment open model. The fast appearance of the metabolite and the Cmax and AUC 0-infinity values higher than those of nerisopam refer to an intensive "first-pass" metabolism. The AUC-dose curves indicate that supposingly the mechanism transforming the N-acetyl metabolites are not as fast as the acetylation.
Acetylation↗
[Human pharmacokinetic study of nerisopam and its n-acetyl metabolite].
It was established during the human phase I study of nerisopam, a new anxiolytic drug, that nerisopam (EGIS-6775) shows two, while N-acetyl metabolite (EGIS-7649) shows one compartmental pharmacokinetic behaviour. Acetylation of nerisopam is polymorph, so that volunteers belonging into slow or fast acetylating group show significantly different plasma concentration. Observed pharmacokinetic differences are primarily manifested in the absorption phase, and not in the elimination one. Accordingly, slow acetylators have higher nerisopam levels, while fast acetylators possess higher metabolite levels. Elimination phase is practically parallel for both compounds. At the same time, significant differences are found in the AUC and Cmax values. Nerisopam is rapidly absorbed, but N-acetyl metabolite is appeared especially fast in the blood. Our consideration is, that nerisopam undergoes significant "first-pass" metabolism process, the extent of which is different between the two acetylator phenotypes.
Acetylation↗
Capillary electrophoretic separation of clomiphene isomers using various cyclodextrins as additives.
The cis (Z) and trans (E) isomers of clomiphene were separated using capillary electrophoresis. Various derivatives of cyclodextrins (CDs) were applied as buffer additives, achieving a resolution of greater than 18. The effect of various parameters, type and concentration of CDs, type and concentration of background electrolytes (BGEs), pH, and organic modifiers has been studied systematically. Migration reversal was observed in several cases. The load ability of the various buffer systems was also taken into account.
Buffers↗
Study of the bone marrow penetration of radioactivity after oral administration of radiolabelled girisopam (EGIS-5810) in mice.
Girisopam (EGIS-5810) is a potent anxiolytic compound. Recent in vitro studies with the substance, in Chinese hamster ovary cells, indicated dose-dependent mutagenic activity. At the same time, in ex vivo bone marrow micronucleus tests performed after treating CFLP mice with extreme oral doses (875, 1300 and 1750 mg/kg) no mutagenic activity could be observed at any of the dose-levels. On the basis of the above results, it seemed reasonable to study the absorption and distribution of radioactivity and particularly its bone marrow penetration after administering tritiated and 14C-labelled girisopam at the same doses as those applied in the micronucleus test. The animals were sacrificed 30 minutes, 2 and 24 hours after treatment and the radioactivity content of blood, plasma and bone marrow was determined. For whole body autoradiography studies, the animals were sacrificed at the same time points, however they were treated with tritium-labelled girisopam. The results indicated that the absorption of radioactivity from the gastro-intestinal tract of the animals started immediately. The samples collected had well measurable radioactivity even 30 minutes after treatment. At the same time, it was also evident, that, in spite of the high doses, the absolute amount of radioactivity was rather low. At both dose-levels, the radioactivity concentration was the highest in samples collected 24 hours after treatment. This results indicated extremely delayed absorption. The radioactivity level of bone marrow was practically the same as that measured in blood. The samples of animals treated with the high-dose had higher radioactivity content, however the increase was not linearly proportional to the dose. Disproportionality can probably be explained by delayed absorption. The whole body autoradiography was in good agreement with the results of quantitative determinations. This results confirmed the observations obtained by ex vivo micronucleus test. The radioactivity penetrated in the bone marrow resulting a long time exposure of the radioactivity without any mutagenic effect.
Administration, Oral↗