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Mass spectra have been obtained for a number of substituted imidazoles using electron impact ionization and ammonia chemical ionization. Iodination of 1,2-[2H2]imidazole gave rise to diiododideuteroimidazole, suggesting iodination had taken place in the 4,5 positions and not 2,4 as previously thought. This compound was examined using both ammonia and [2H3]ammonia as reagent gases. Exchange of H-1 and partial exchange of iodine for proton was shown to occur in the chemical ionization source. A number of isomeric halomethyl-nitroimidazoles were also examined to explain observed differences in the spectra. The 4-nitroimidazoles apparently fragment to give an aziridinone ion, whereas the 5-nitro isomers appear to fragment to a cyclopropenone. Substitution of the halogen in the nitroimidazoles does not appear to occur so readily.

The mass spectra of disopyramide phosphate and two stable isotopically labelled analogues have been obtained using electron impact and chemical ionization. The low isotopic purity of [13C, 15N] disopyramide phosphate was shown to be due to the low isotopic purity of the 15N label. A stable isotope dilution assay for disopyramide and [13C, 15N] disopyramide in biological fluids has been developed using [2H14] disopyramide phosphate as the internal standard. This assay will be used to analyse samples obtained after the co-administration of disopyramide phosphate intravenously and [13C, 15N] disopyramide phosphate orally to several animal species.

The stable isotope co-administration technique for estimating the bioavailability of drugs has been investigated in a series of experiments using rhesus monkeys. The compound chosen for study was disopyramide phosphate. A cross-over study was designed whereby the animals received disopyramide phosphate (administered intravenously at 5 mg kg-1) and [13C, 15N] disopyramide phosphate (administered orally at 5 mg kg-1), with a wash-out period between doses. A co-administration study was carried out whereby both the oral and intravenous doses were administered together. The co-administration study was repeated. The results from the cross-over study showed [13C, 15N] disopyramide to have an oral availability of 4.9±0.9% (by comparing areas under the plasma concentration versus time curves). The bioavailability was estimated to be 5.7±0.3% comparing totals excreted in urine over 48 h. The bioavailability of the oral dose was calculated as 8.2±2.5% (comparing areas under plasma concentration versus time curves) and 9.3±3.0% (comparing totals excreted in urine) after co-administration. The differences between these results and the cross-over results were examined in a further study, using oral administration only. The animals were dosed orally with a solution containing both disopyramide phosphate (5 mg kg-1) and [13C, 15N] disopyramide phosphate (5 mg kg-1). No differences were observed between the plasma concentration versus time curves or urinary excretion for either isotope. It is unlikely that the discrepancy in bioavailability is due to absorption, metabolism or excretion of the oral dose. It is probable that the high concentration of disopyramide obtained after the intravenous dosage affects the disposition of the oral dose, and this gives the higher figure.

An assay for the quantitative analysis of six biologically important prostanoids based on combined gas chromatography negative ion chemical ionization mass spectrometry has been developed. Prostanoids were extracted from biological fluids by liquid chromatography on Sep-Pak cartridges and converted to pentafluorobenzyl ester derivatives. Samples were injected on capillary columan by the splitless technique and injections were made in a high boiling hydrocarbon solvent (n-dodecane) in order to minimize chromatographic run times. Quantification was carried out using selected ion monitoring of the appropriate [M-pentafluorobenzyl]-anion. The assay has been used for profiling cyclooxygenase metabolites of arachidonic acid in guinea pig lung perfusate after induction of anaphylaxis and platelet rich plasma after collagen-stimulated aggregation.

Electron capturing pentafluorobenzyl ester derivatives of prostanoids provide intense negative ion chemical ionization mass spectra. Fragmentation is directed almost entirely away from the prostanoid molecule and this provides intense [M - C6F5CH2]-ions. These ions are ideal for specific and sensitive quantitative selected ion monitoring analysis. The limits of sensitivity employing this technique are in the range 1–8 pg on column compared with 100–500 pg using the corresponding methyl ester derivative in the electron impact mode. The capillary column characteristics of the pentafluorobenzyl esters are suitable for the development of multiprostaglandin gas chromatographic mass spectrometric assays.

Reaction of debrisoquine and 4-hydroxydebrisoquine with hexafluoroacetylacetone to form pyrimidinyltetrahydroisoquinolines is used as the basis for a gas chromatographic mass spectrometric assay for these two compounds. The electron impact, positive ion chemical ionization and electron capture negative ion chemical ionization mass spectra of these pyrimidinyltetrahydroisoquinolines are described and compared. The latter were found to give an intense response under electron capture negative ion chemical ionization conditions, thus allowing the development of a much more sensitive assay for debrisoquine and 4-hydroxydebrisoquine. Derivatives of the hydroxyl group in 2-(4',6'-bistrifluoromethyl-2'-pyrimidinyl)-4-hydroxytetrahydroisoquinoline were synthesized with a view to further improving the electron capture negative ion chemical ionization response. The resulting mass spectra showed extensive fragmentation for perfluoroacyl esters and halogenated silyl ethers. Only dimethylsilyl and trimethylsilyl ethers gave similar spectral responses to the parent compound.

The dimethyl derivatives of clonidine and [2H4]clonidine give good chemical ionization mass spectra when ammonia is used as reagent gas. A gas chromatographic mass spectrometric selected ion monitoring assay for the estimation of clonidine in plasma and urine using ammonia chemical ionization is described.

A carrier effect has been shown to exist in a stable isotope dilution assay for diphenoxylate. When a tetradeuterated analogue is used as a carrier and internal standard a sevenfold increase in sensitivity is observed for the unlabelled compound. Examination of a related pharmacologically active compound (SC-27166) showed a much smaller effect.