Gas chromatographic-mass spectrometric method for quantitative determination of ketotifen in human plasma after enzyme hydrolysis of conjugated ketotifen.

A validated method for determination of total amount of ketotifen (unchanged and conjugated) in human plasma has been presented. An enzyme hydrolysis of conjugated ketotifen was conducted with combination of beta-glucuronidase and arylsulfatase. After the enzyme hydrolysis a solid-phase extraction was applied as a cleaning step. The quantitative determination by gas chromatography with mass-spectrometry detection (GC-MS) was performed. Pizotifen has been used as an internal standard. A reliable hydrolysis as well as a satisfactory accuracy, improved precision in the linear region from 0.500 to 10.0 ng/ml plasma, limit of detection of 0.010 ng/ml and prolonged capillary column life have been achieved.

Effect of cimetidine on the pharmacokinetics of the metabolites of metamizol.

Metamizol (dipyrone) is hydrolyzed in the gastrointestinal tract to the pharmacologically active metabolite 4-methyl-amino-antipyrine (4-MAA), which is transformed by both, oxidation to 4-formyl-amino-antipyrine (4-FAA) and demethylation to 4-amino-antipyrine (4-AA). 4-AA is acetylated to 4-acetyl-amino-antipyrine (4-AcAA). The aim of the present study was to investigate whether cimetidine will alter the pharmacokinetics of the metabolites of metamizol due to cimetidine-induced inhibition of the metabolic transformation of 4-MAA. The study was carried out in 12 patients with duodenal ulcer treated with cimetidine 1,000 mg daily over 20 days. A single oral dose of metamizol 1,500 mg was administered 2 days prior to commencement of cimetidine therapy to all patients. Two further doses of 750 and 1,500 mg of metamizol were given in a randomized order on days 8 and 13 during cimetidine treatment. Blood samples for determination of metamizol metabolites were drown over 48 hours post dose. Drug assays for metamizol metabolites and cimetidine were performed using HPLC methods. The patients were phenotyped for CYP2D6 and acetylation polymorphism. The results revealed that cimetidine interacted with 4-MAA by increasing the systemic availability, prolonging the elimination half-life and decreasing the systemic clearance of 4-MAA, whereas the renal clearances of 4-MAA remained unchanged. Consistent with cimetidine-induced changes in the oxidation of 4-MAA to 4-FAA, as well as in the demethylation of 4-MAA to 4-AA, were the decreased rates of production and the lower maximum concentrations of 4-FAA and 4-AA when metamizol was administered during cimetidine treatment (p < 0.05). No correlation was found between the decrease in the production rates of 4-FAA induced by cimetidine and the hydroxylation abilities of the patients, this suggesting that CYP2D6 is not involved in the metabolism of 4-MAA to 4-FAA. The acetylation of 4-AA to 4-AcAA was not affected by cimetidine. Cimetidine produced an increase not proportional to the dose in the systemic availability only of 4-MAA, whereas the kinetics of the other metabolites changed proportionally to the increasing dose of metamizol.

Improved gas chromatographic-mass spectrometric method for the quantitative determination of vinpocetine in human plasma.

An improved and validated method for the determination of vinpocetine in human plasma using a combination of a solid-phase extraction as a cleaning step followed by gas chromatography-mass spectrometry (GC-MS) has been presented. Quantitation has been carried out with apovincaminic acid methyl ester as internal standard. A limit of detection of 0.01 ng/ml, limit of quantitation of 0.10 ng/ml, as well as a satisfactory accuracy, improved precision and prolonged capillary column life have been achieved.

Comparative bioavailability of two oral metamizole formulations. Influence of the acetylation phenotype.

The bioavailability of the four metabolites of metamizole (CAS 68-89-3), 4-methyl-amino-antipyrine (4-MAA), 4-formyl-amino-antipyrine (4-FAA), 4-amino-antipyrine (4-AA) and 4-acetyl-amino-antipyrine (4-AcAA) was compared after oral administration of a test (Analgin) and a reference formulation, both containing 1 g of metamizole. The study was conducted in 12 healthy volunteers according to an open, randomized, cross-over design. The geometric mean of the area under the serum concentration-time curves (AUC) of 4-MAA for the test formulation was 87.61 (57.58-133.30) micrograms.h/ml and was similar to that for the reference formulation (86.83; 53.86-139.92 micrograms.h/ml). No statistically significant differences between test and reference formulation were found with respect to the rate of absorption (Cmax, tmax, 100 Cmax/AUC) of 4-MAA. For 4-FAA, 4-AA and 4-AcAA, the 90% confidence intervals of the bioavailability parameters lay also within the bioequivalence ranges. Four of the subjects were rapid and eight were slow acetylators. No differences were found between slow and rapid acetylators in the bioavailability of 4-MAA, the pharmacologically active metabolite of metamizole.

[Pharmacokinetic effects of the preparation pyramem on experimental animals]. / Prouchvane vûrkhu niakoi farmakokinetichni otnasianiia na preparata piramem v opitni zhivotni.

The authors examined resorption and distribution of the preparation pyramem (2-oxo-1-pyrrolidinacetamide), synthesized by RICPI and the obtained data were compared with literary data on the preparation pyracetam. Gas chromatographic method, described in the literature, was introduced for determination of concentration of pyracetam in plasma using some modifications. The obtained results and the pharmacokinetic parameters, estimated on the basis of the results, showed good coincidence with those reported in literature. The established quick resorption, the course of plasma curves after oral and venous application and biologic half-life of pyramem in rats gave foundation to conclude that the synthesized by RICPI 2-oxy-1-pyrrolidinacetamide was identical with preparation pyracetam.