Determination of tolterodine and the 5-hydroxymethyl metabolite in plasma, serum and urine using gas chromatography-mass spectrometry.

A specific and sensitive capillary gas chromatography-mass spectrometry assay for the determination of tolterodine and the 5-hydroxymethyl metabolite (Labcode DD 01) in plasma, serum and urine is described. Extraction of the analytes was performed with liquid/liquid or solid-phase extraction prior to derivatisation with a silyl reagent. The derivatives were quantified by selected ion monitoring mass spectrometry using deuterium-labelled internal standards. A single level calibration curve was utilised for quantification of plasma, serum and urine concentrations of tolterodine and DD 01. The accuracy (inter- and intra-day) for both analytes was within 87-110% in the range 0.5 and 50 ng ml-1 and precision was better than 90%. Overall, this method was shown to be reliable for pharmacokinetic assays of tolterodine and the metabolite DD 01 in samples from preclinical and clinical studies.

Absorption of tranexamic acid as a prodrug in healthy volunteers.

The absorption of trans-4-(aminomethyl)cyclohexanecarboxylic acid (tranexamic acid, Cyklokapron) administered as the prodrug trans-4-(aminomethylcyclohexanecarboxylate hydrochloride (Kabi 2161) was investigated in 3 healthy volunteers. Kabi 2161 was given orally in doses of 1, 2, 3 and 3.5 mmol, respectively, and as a reference a clinical dose of 1.5 g tranexamic acid (9.6 mmol) was administered. At 3 mmol of Kabi 2161 the same maximum plasma concentration of tranexamic acid was obtained as with the reference drug but with Kabi 2161 it appeared earlier. The recovery of tranexamic acid in the urine 0-48 h after administration of Kabi 2161 was 84.7, 82.4, 89.4 and 97.5%, resp., of the increasing doses. For the tranexamic acid 37.0% could be recovered. A similar result was seen in the areas under the plasma concentration-time curves normalized for dose. With Kabi 2161, 13.1, 19.6, 14.4 and 14.3 mg.h/l.mmol were found compared to 8.0 mg.h/l.mmol with tranexamic acid. From these results it was concluded that Kabi 2161 markedly increased the bioavailability of tranexamic acid in man.

Applicability of a cryogradient technique for the enrichment of PAH from automobile exhausts: demonstration of methodology and evaluation experiments.

A cryogradient system for the enrichment of polycyclic aromatic hydrocarbons from gasoline and diesel powered vehicles is described. The sampling involves particle trapping on a filter followed by gas phase enrichment in three separate condensers. The filter is extracted with dichloromethane (DCM). For the extraction of the condensers three different solvents have been used; cyclohexane, acetone and DCM. The latter has also been used together with three buffers, pH 3, pH 7 and pH 11. Analyses of polynuclear aromatic hydrocarbons were performed by means of glass capillary gas chromatography and mass spectrometry. These analyses of diluted gasoline exhausts show that of the phenanthrene/anthracene, fluoranthene/pyrene and their monoalkylated forms found, between 90 and 30% are present in the gas phase. For diesel emissions, corresponding values are between 50% and 5%, respectively. However, the distribution of PAH between gas phase and particles is dependent on dilution ratio and filter temperatures. The addition of NO2 (approximately 7 ppm) prior to filter sampling involves degradation of cyclopenteno(cd)pyrene (CPedP) and benzo(a)pyrene (BaP) on the particles from diluted gasoline exhausts. This also occurs with BaP on diesel particles sampled under equivalent conditions. Mutagenicity data from these experiments support the theory of formation of direct-acting mutagens, probably due to nitration. Parallel sampling of particles with Teflon-coated and glass fiber filters does not show that components which are reactive to NO2, e.g., CPcdP, are degraded to a lower extent when glass fiber filters are used.

Emission of carcinogenic components with automobile exhausts.

Different sampling methods for mutagenic polynuclear aromatic hydrocarbons (PAH) are described. These methods involve either direct sampling of raw exhausts which prior to filtering are cooled in a condenser, or filter sampling of exhausts diluted in a tunnel. The relevance of gas-phase PAHs of samples from diluted exhausts is discussed; methods used are either adsorbents (XAD-2) or cryogenic condensation. The emission of benzo(a)pyrene and certain other PAHs is reported from vehicles using different fuels (gasoline, diesel, LPG, alcohols) or different emission control systems. The emission of some volatiles, such as benzene, ethylene and alkylnitrites, is also presented from different types of fuels used.