ABSTRACT
RGH-1756 (1-(2-methoxy-phenyl)-4-(4-[4-(6-imidazo[2,1-b]-thiazolyl)-phenoxy]-butyl)-piperazine dimethansulphonate) is a novel atypical antipsychotic candidate of Gedeon Richter Ltd. A new HPLC method has been developed and validated for the quantitative determination of RGH-1756 in dog and rat plasma. The compound and the internal standard are extracted from the biological samples by a simple and fast liquid--liquid extraction method, using 1-chlorobutane. The recovery for RGH-1756 is about 90%. The extracts are analyzed by reversed phase HPLC (column: Supelcosil-LC-18-DB 250*4.6 mm, 5 microm, eluent:acetonitrile:methanol:0.2 molar ammonium-acetate 40:25:35, lambda=254 nm). The assay is specific for RGH-1756. The standard curves are linear in the range between 10 and 2000 ng ml(-1). The overall precision (expressed as CV%) and accuracy (expressed as bias%) of quality controls and calibration standards are within 15%. The validated lower limit of quantification is 10 ng/ml. No indications have been found for possible instabilities of RGH-1756 in plasma, in the extraction solvent, or after repeated thawing-freezing cycles. The method has been succesfully applied for the bioavailability studies of RGH-1756 in the two animal species. In these studies results of the inprocess method validation have shown the reliability of the method, too. CV% of quality controls in the rat study has been found between 7.4 and 10.0%, in the dog study between 4.1 and 12.5%. The bias has ranged from 0.4 to 3.8% and from -4.5 to 1.2% in the rat and dog study, respectively.
Subject(s)
Antipsychotic Agents/blood , Chromatography, High Pressure Liquid/methods , Piperazines/blood , Spectrophotometry, Ultraviolet/methods , Thiazoles/blood , Animals , Antipsychotic Agents/pharmacokinetics , Biological Availability , Calibration , Dogs , Female , Male , Piperazines/pharmacokinetics , Rats , Rats, Wistar , Reproducibility of Results , Sensitivity and Specificity , Thiazoles/pharmacokineticsABSTRACT
In the present study distribution and elimination of RGH-5002--a new centrally acting muscle relaxant--were investigated in rats by using 14C-labelled compound. Whole-body autoradiography and quantitative determination of the radioactivity in various organs following single and repeated oral administration of [14C]RGH-5002 demonstrated extensive distribution of the drug with high levels in the gastrointestinal tract, kidneys, liver, endocrine and exocrine glands and lungs. Minimal accumulation was observed after repeated (8 days) administration. The same distribution characteristics were observed in both sexes. In pregnant rats radioactivity appeared in the placenta and fetal tissues. Elimination was investigated by measuring radioactivity in 24 h fractions of urine and faeces after single dose administration of the drug. The larger portion of radioactivity was excreted in the urine (81.67 +/- 1.61% of the dose). The faecal recovery was 11.12 +/- 1.19% of the administered dose. Approximately 80% of the excreted radioactivity was recovered within the first 24 hours.
