V. Ščasnár

Radiochemical assay of stability of14C-cytostasan solutions during preparation and storage

Cytostasan, 5-[Bis(2-chloroethyl)amino]-1-methylbenzimidazolyl-2-butyric acid, is an antineoplastic agent which degrades spontaneously in water solutions yielding two hydrolysis products, monohydroxy- and dihydroxycytostasan. We developed a stability-indicating radiochemical assay based on ion-pair extraction to investigate the stability of solutions of14C-cytostasan under conditions that might be expected when the drug is being prepared and stored for pharmacokinetic studies in animals. The possibility of using the distribution coefficient of14C-cytostasan as an indicator of stability was investigated in the extraction system benzene-dicarbolide of cobalt-0.5N HClO4. The mechanism of extraction is believed to be that of ion-pair forming process between the hydrophobic anion and the protonized cytostasan. Since no extraction of hydroxy derivates was observed the value of the distribution coefficient of the parent drug appears to be a suitable indicator of the stability of14C-cytostasan solutions.

Ion-pair extraction of pentacaine from biological materials

Simple and rapid extraction method for quantitative and selective isolation of the new local anesthetic pentacaine from biological materials is proposed. The technique of ion-pair formation was found to be more effective than usual access using the extraction of the nonionized species. The extraction yield of the unchanged molecule3H-pentacaine after double extraction and single scrubbing was found to be more than 90%. The radiochemical purity was over 90%. The method appears suitable for pharmacokinetic studies in the animal body.

Extraction of137Cs by cobalt dicarbolide

The possibility of the use of chlorinated cobalt dicarbolide, H+C4B18H15Cl7Co−, it nitrobenzene for the selective extraction of137Cs from mixtures of95Zr−95Nb,106Ru-106Rh and144Ce was studied. The effect of aqueous phase acidity on the distribution ratio of Cs, Ru and Zr as well as the effect of the amount of isotopic and non-isotopic carriers of alkali metals on the distribution ratio were determined. Separation factors for cesium from ruthenium, zirconium and cerium were calculated, all being extracted from nitric acid solutions. The efficiency of cesium separation was verified by gamma-spectrometry.

Solvent extraction and radiometric determination of3H-stobadine in biological material

A simple and rapid radiochemical method for the efficient and selective isolation of3H-stobadine from plasma, urine and organ homogenates has been developed. The method comprises the extraction of3H-stobadine from the biological matrix containing 2M Na2CO3 into n-hexane followed by scrubbing of partly coextracted metabolites into an equal volume of 2M Na2CO3. The specificity of the procedure presented is demonstrated by TLC and the comparison of distribution coefficients of authentic and apparent (isolated) substances.

Fluorimetric assay of stobadine in serum of dogs

In the present paper a specific fluorimetric assay is now described for the determination of stobadine in serum of dogs. The assay involves the first step of the radiochemical method. The comparison of the proposed fluorimetric assay and the previously developed radiochemical method demonstrates that both methods yielder similar serum-time curves after both routes of administration (oral or intravenous) of stobadine

Extraction-chromatographic separation of137mBa from137Cs

The possibilities of extraction-chromatographic separation of137mBa from137Cs in genetic succession were studied, using columns filled with support beads loaded with the extractant H+[π)−(3)−1,2−B9C2H11]2Co−, further referred to as dicarbolide-H+, in nitrobenzene. The dependence of the amount of separable activities on experimental conditions was established. Optimal conditions were selected for the separation process. The effects of isotopic and nonisotopic carriers of137mBa on the separation and the degree on saturation of extraction-chromatographic column with Ba2+ ions were evaluated. The effects of acidity of the elution solutions, of flow-through velocity, the amount of elution solution and the quality of carrier beads on the separation process were assessed. The extraction-chromatographic yield was calculated and the number of possible repeated elution cycles for137mBa with saline and some other eluents was determined.

Isolation of137Cs from excreta by dicarbolide of cobalt

Extraction by polyhedral complex compound of the formula H+ [(π-(3)-1,2-B9C2H11)2Co−] further on referred to as dicarbolide-H+ and its chloro-derivate H+[B18C4H15Cl7Co−] further on referred to as Cl-dicarbolide-H+ in nitrobenzene was used for the analysis of137Cs in urine and faeces after internal contamination. The dependence of distribution ratio on the acidity of analysed solutions was determined. The effect of urine dilution was assessed as well as the effect of various concentrations of the extraction agents on the distribution ratio of137Cs. The effect of phase ratio at the different concentrations of isotopic carrier was assessed, as well as the effect of potassium ions on the decrease of the distribution ratio at the extraction of137Cs by dicarbolide-H+ or its chloro-derivate. The possibility of isolation of137Cs by extraction and the isolation of137Cs by ion-exchange absorbents and by ammonium molybdophosphate was compared. The values of distribution coefficient were determined at various concentrations of nitric acid and the isotopic carrier. The dependence of coextraction of some activated radionuclides and fission products by dicarbolide-H+ on the nitric acid concentration in the solute was determined. The effect of mass of contaminated faeces on the value of the distribution ratio of137Cs by the extraction was evaluated. As a result, a suggestion was given for the rutine isolation procedure of137Cs extraction with dicarbolide-H+ from the excreta contaminated by a mixture of radionuclides.

Irradiation of the head by 60Co opens the blood-brain barrier for drugs in rats.

The passage of 6 model drugs; acetylsalicylic acid, chloramphenicol, ethimizol, carbisocaine, heptacaine, and diazepam, through the blood-brain barrier, was determined in unirradiated control rats and in animals 1, 3, and 7 days after irradiation of the head only with a dose of 25 Gy from a60Co source. The brain uptake index (BUI), which compares the uptake of the test substance with that of3H2O 5 s after their injection into the common carotid artery, was significantly increased in comparison with unirradiated controls 7 days after irradiation, for all substances tested except for ethimizol. For acetylsalicylic acid and chloramphenicol it was also significantly increased in the other time intervals. The less lipophilic substances showed a greater relative increase of BUI than the more lipophilic ones.

Separation of137Cs and90Sr from mineralizates of biological materials by dicarbolide of cobalt

The distribution of some radionuclides in the course of137Cs and90Sr extraction and scrubbing between organic and water phase was determined.137Cs and90Sr were isolated from the mixture of radionuclides in mineralized biological materials. Dicarbolide of cobalt i. e. 3,3′-commo-bis[undecahydro-1,2-dicarbo-3-closo-dodecaborate] was used as an extracting agent. Quantities of the extracted radionuclides were determined by gamma spectrometric technique. Single and repeated extraction of90Sr with 0.01M resp. 0.1M dicarbolide of cobalt in nitrobenzene and scrubbing of coextracted radionuclides by 0.5M HNO3 were studied. The extraction of90Sr was investigated from solutions of a hydrofobizing agent in the same way. Finally, the quantitative extraction of137Cs followed by the extraction of90Sr from mixtures of radionuclides in a mineralized biological material was studied. Extraction yields from dry and wet mineralizates of biological tissues, from urine and milk were compared. Suitable working conditions for the separation procedures were selected.

Pharmacokinetics of carbisocaine in rats and mice

Summary[14C]carbisocaine, N-(2-(2-[1-14C]-heptyloxyphenylcarbamoyloxy)-propyl)-diethylammonium chloride was administered to male Wistar rats, weighing 180–210 g IV in doses of 0.425, 1.425, 2.425 or 4.425 mg/kg or orally in a dose of 2.425 mg/kg. Extraction of carbisocaine from alkaline media into n-heptane was used for assessment of the unchanged drug in plasma, organs and excreta in predetermined time intervals. The two-way analysis of variance confirmed the insignificant effect of subject variability of experimental animals (p > 0.05) on plasma data after IV administration. Plasma data following the IV administration were approximated by a linear open two-compartment model with elimination from the central compartment. Regression analysis indicated linearity between carbisocaine plasma AUC and the IV administered dose within the range tested. The following model parameters were obtained: elimination half-life 161.2±37.5 min, total body clearance 59.5 ml/min/kg, distribution volume in steady state 5616.2 ml/kg and mean residence time 96.7 min. The systemic availability of the orally given carbisocaine was 45.2%, assessed by AUCpo/AUCiv (0–360 min). The brain uptake index of carbisocaine in relation to3H2O was 57.7±3.9%. Whole body autoradiographs of mice injected with [14C] carbisocaine documented accumulation of14C in gall and urinary bladder and in the gut contents and the effective placental barrier against carbisocaine and its metabolites.