Micro liquid chromatography-mass spectrometry with direct liquid introduction used for separation and quantitation of all-trans- and 13-cis-retinoic acids and their 4-oxo metabolites in human plasma.

The separation and quantitation of the pentafluorobenzyl derivatives of all-trans- and 13-cis-retinoic acids and their 4-oxo metabolites in human plasma on micro high-performance liquid chromatographic columns (0.32 mm I.D.) is described. The column outlet was directly coupled to the source of a quadrupole mass spectrometer via a simple SFC-frit interface. Negative ion chemical ionization conditions were obtained by coaxial introduction of ammonia as a reagent gas. A signal-to-noise ratio well above 3 was obtained for 1 pg of each analyte injected. The limit of quantitation calculated from spiked biological plasma extracts was 0.3 ng/ml.

Determination of the new aromatic retinoic acid Ro 13-7410 in plasma by two-dimensional gas chromatography negative ion chemical ionization mass spectrometry with selected-ion monitoring.

A highly sensitive and specific method for the determination of the aromatic retinoic acid Ro 13-7410 in plasma at the picogram per millilitre level is described. The method involves extraction of plasma using Extrelut-1 columns, purification of the extract with Bond Elut-NH2 cartridges, derivatization with pentafluorobenzyl bromide, and subsequent analysis by two-dimensional capillary gas chromatography using the zone-cutting technique, stable isotope dilution and selective negative ion monitoring chemical ionization mass spectrometry. A tetradeuterated analogue is used as internal standard. Quantification is possible down to 25 pg/ml using 1 ml of plasma. The coefficients of variation of the method as calculated from quality control samples are 8.5 and 4.2% at the 100 and 400 pg/ml levels. The method has been applied to the analysis of plasma of volunteers following an oral dose of 40 micrograms Ro 13-7410 and plasma of dogs following an intravenous and oral dose of 25 and 50 micrograms, respectively.

Occurrence of pharmacologically active benzodiazepines in trace amounts in wheat and potato.

Aqueous acid extracts of wheat grains and of potato tuber were found to contain a series of compounds displaying a high affinity to the central type benzodiazepine receptor (BZR) in mammalian brain. Further analysis using different HPLC systems, as well as mass spectrometry and gas chromatography combined with mass spectrometry lead to the identification of compounds belonging to the classical 5-phenyl-1,4-benzodiazepinones. In wheat grains diazepam, N-desmethyldiazepam, delorazepam, deschloro-diazepam, delormetazepam, lormetazepam and isodiazepam were identified, while potato tuber contained diazepam, N-desmethyldiazepam, delorazepam, lorazepam and delormetazepam. The concentration of the benzodiazepines (BZ) was in the low ppb range. Their biosynthesis most probably takes place in the plant tissue. The availability of BZs in plant nutritives points to a possible source for the previously reported presence of BZ in brain and peripheral tissues of several animal species and man.

Studies of mefloquine bioavailability and kinetics using a stable isotope technique: a comparison of Thai patients with falciparum malaria and healthy Caucasian volunteers.

1 A mefloquine hydrochloride tablet (250 mg base equivalent to 4.8 +/- 0.6 mg kg-1; mean +/- s.d.) and deuterium labelled mefloquine hydrochloride solution (250 mg base) were given to six adult male Thai patients with acute falciparum malaria and six healthy Swiss adult male volunteers (equivalent to 3.5 +/- 0.1 mg kg-1). 2 The relative bioavailability of the tablet formulation derived from comparison of the areas under the plasma concentration-time curves was similar in both groups; 87 +/- 11% and 89 +/- 10% (mean +/- s.d.). 3 The rate of drug absorption appeared to be similar in the two groups but peak plasma mefloquine concentrations were approximately three times higher in the Thai patients (1004 +/- 276 ng ml-1 for the tablet and 1085 +/- 280 ng ml-1 for the suspension) compared with the Swiss volunteers (319 +/- 73 ng ml-1 for the tablet, and 369 +/- 121 ng ml-1 for the suspension). 4 Estimates of the oral clearance CLpo of unlabelled mefloquine were significantly lower (17.5 +/- 4.4 ml h-1 kg-1) in the Thai patients compared with 28.8 +/- 3.5 ml h-1 kg-1 in the Swiss volunteers; P less than 0.05). Terminal elimination half-lives were significantly shorter in the patients (10.3 +/- 2.5 days) than in the volunteers (16.7 +/- 1.9 days; P less than 0.005). Differences of a similar magnitude were observed when comparing the pharmacokinetic parameters derived from the deuteromefloquine plasma concentrations. 5 Both genetic and disease related factors are likely to account for the large pharmacokinetic differences between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Pyrrolidinone and succinimide endogenously present in several mammalian species.

2-Pyrrolidinone and succinimide were identified in blood plasma of man, rat, and mouse. Dog plasma contained only traces of 2-pyrrolidinone not exceeding significantly the detection limit of our GCMS-method. Succinimide but not 2-pyrrolidinone could also be found in the brains of rat and mouse. Evidence is presented for a metabolic pathway leading from 2-pyrrolidinone to succinimide, with 5-hydroxy-2-pyrrolidinone as an intermediate.

Highly sensitive and specific determination of mefloquine in biological fluids using gas chromatography mass spectrometry with selected ion monitoring.

A highly sensitive and specific assay for the determination of racemic erythro-alpha-(2-piperidyl)-2,8-bis(trifluoro-methyl)-4-quinoline-methanol in whole blood, plasma and urine has been developed. The method involves the extraction of the drug together with an internal standard, formation of the corresponding O-trimethylsilyl-N-trifluoroacetyl derivatives, gas chromatographic separation and mass spectrometric measurement of the peaks by selected ion monitoring. The method has a sensitivity of 1 ng ml-1 for plasma and 3 ng ml-1 for whole blood or urine. It has been applied to the analysis of mefloquine in plasma following an oral dose of 250 mg of the drug to healthy subjects. No interference was observed from the simultaneous administration of Fansidar.