Tissue distribution and metabolism in rat of an ethynesulphonamide with filaricidal activity.

1. The tissue distribution and metabolism of a new filaricidal agent P903 (N-[(2-phenylethynyl)sulfonyl]morpholine) were studied in rat. 2.

Comparative study of the biotransformation of bepridil analogs in isolated liver cells from one rat. Relationships between structure and in vitro liver toxicity.

The biotransformation of several analogs of the anti-calcium agent bepridil was studied comparatively in liver cells isolated from one rat. Three types of metabolites were identified by mass spectrometry, resulting from three phase I reactions: hydroxylation, N-debenzylation and pyrrolidine ring opening. The amount of each bepridil analog untransformed after 18 h of incubation depended on its liver toxicity rather than on its concentration in the culture medium.

Gas chromatographic-mass spectrometric determination of isosorbide 5-mononitrate in human plasma.

A highly specific and precise method using gas chromatography-mass spectrometry was developed for the measurement of isosorbide 5-mononitrate in plasma using isomannide mononitrate as internal standard. With regard to the numerous analytical problems encountered when organic mononitrates were determined in plasma, such as thermal instability and adsorption, compounds were silylated before gas chromatography. In order to increase the specificity of the assay, two specific ions of the isosorbide 5-monitrate were simultaneously recorded.

Determination of oxeladin in human plasma by gas chromatography--mass spectrometry.

A capillary gas chromatographic method with mass-selective detection was developed for the determination of oxeladin in human plasma. Plasma samples (1 mL) were alkalinized and extracted using 5mL of hexane: isoamyl alcohol (99:1). The method was demonstrated to be sensitive (limit of quantitation at 1 ng/mL), linear between 1 and 150 mg/mL, accurate and precise enough (mean error and mean coefficient of variation at the limit of quantitation were 2.

Disposition and metabolism of O6-alkylguanine-DNA alkyltransferase inhibitor in nude mice bearing human melanoma.

Tumor resistances to chloroethylnitrosourea (CENU) are mainly due to O6-alkylguanine-DNA alkyltransferase (AGT). Our laboratory has synthesized a new water-soluble AGT inhibitor. O6-benzyl-N-acetylguanosine (BNAG).

Determination of phloroglucinol in human plasma by gas chromatography-mass spectrometry.

A specific and sensitive method has been developed for the determination of phloroglucinol in plasma; it involves an optimized procedure for blood sampling designed to minimize the in vitro oxidation of the molecule, and gas chromatography-mass spectrometry after silylation of the compound. The method allowed a reliable determination of phloroglucinol in plasma. The precision and accuracy of the assay, reported as coefficients of variation, were below 15%.

Measurement of trazodone in plasma and brain of rat by capillary gas chromatography with a nitrogen-selective detector.

A specific and highly sensitive method for the measurement of trazodone in plasma and brain of rat is presented. The compound and the internal standard were extracted from alkalinized samples with hexane and analysed by capillary gas chromatography with nitrogen-selective detection. The method was demonstrated to be accurate and precise.

Biotransformation study of para-substituted phenylpiperazines in beagle dogs by gas chromatography-mass spectrometry.

1. Beagle dogs were treated orally (10 mg/kg) with para-chloro-, para-fluoro- and para-methyl-phenylpiperazine derivatives, and urine was collected for 72 h after treatment. 2.

Identification of several human urinary metabolites of 6-benzoyl benzoxazolinone by gas chromatography/mass spectrometry.

The biotransformation of 6-benzoyl benzoxazolinone (6-BB), a non-narcotic peripheral analgesic, was studied in eight healthy volunteers after oral administration of a single dose of 1 g. Urinary metabolites were extracted either with ethyl acetate at different pH values or by percolating at pH 5 through Amberlite XAD 2 ion-exchange resin. Eluates were concentrated under vacuum, purified by thin-layer chromatography and analysed by gas chromatography/mass spectrometry or direct insertion probe mass spectrometry.

N-dephenylated and N-phenyl urinary metabolites of mociprazine (CERM 3517) in beagle dogs after oral administration. A mass spectrometric determination.

CERM 3517 (mociprazine), a new anti-emetic compound, was administered orally to six beagle dogs at 10 mg/kg b.i.d.

Kinetics of allopurinol and its metabolite oxypurinol after oral administration of allopurinol alone or associated with benzbromarone in man. Simultaneous assay of hypoxanthine and xanthine by gas chromatography-mass spectrometry.

Allopurinol, oxypurinol, hypoxanthine and xanthine were assayed simultaneously using a highly specific method combining gas chromatography and mass spectrometry. Two hypo-uricaemic prescriptions were compared: i) 300 mg of allopurinol (AL); and ii) 100 mg of allopurinol plus 20 mg of benzbromarone (AL + BZB). When administered acutely, their effects on blood uric acid levels were similar.

Plasma and blood assay of xanthine and hypoxanthine by gas chromatography-mass spectrometry: physiological variations in humans.

Plasma and blood xanthine and hypoxanthine levels were assayed using a sensitive and specific method involving gas chromatography-mass spectrometry, associated with an optimized sample preparation procedure. Physiological variation was studied in 224 subjects with no purine metabolism disorders. An age dependency for both compounds was found, comparable with that known for uric acid.

Chronopharmacokinetic and bioequivalence studies of two formulations of trimipramine after oral administration in man.

The bioavailability of two oral formulations of trimipramine, tablets and solution, was performed in twelve healthy volunteers, in a cross-over study. Each formulation was administered in the morning after a fasted period, and in the evening after a meal, in order to evaluate the role of both administration time and food consumption on the plasma kinetic parameters, under usual therapeutic conditions. A high interindividual variability of data was found.

Pharmacokinetics of metapramine and its demethylated metabolites in plasma and brain of mice.

Previous studies on pharmacokinetic parameters of tricyclic antidepressants (TCAs) in rodents have shown different results from those obtained for the same drugs in man. The kinetics of metapramine (META) and its major demethylated metabolites (METs) were studied in the SWISS CD 1 mouse after acute administration in order to establish the pharmacokinetic parameters in plasma and brain. The plasma half-life (T1/2) was very short (87 min) compared with the half-life (7 h) in man.

Disposition and metabolism of letosteine in rats.

The metabolism and disposition of letosteine, labeled either with 14C or 35S, has been investigated in Sprague-Dawley rats. In separate experiments, rats received 20 mg/kg, iv or orally, [14C]letosteine or [35S]letosteine. Radioactivity was rapidly excreted, mainly in urine, after iv and oral administration.

Pharmacokinetics of cyclophosphamide administered alone or in combination with vindesin or cisplatin in 5 patients with bronchial adenocarcinoma.

The pharmacokinetics of cyclophosphamide (CPH) administered intravenously at doses between 200-400 mg alone or in combination with vindesin (VDS) or cisplatin (cisPt) were studied in 5 patients who had bronchial adenocarcinoma, with normal liver and kidney functions. The linearity and the reproducibility of CPH kinetics were confirmed and its pharmacokinetic parameters were found to be unaffected by simultaneous or sequential administration of either vindesin or cisplatin. Total clearance was 7.

Main excretion metabolites of 7-methoxy-2-nitronaphtho[2,1-b]furan (R 7000) in rats.

Major metabolites, isolated from rat bile and urine after administration of a single dose of 7-methoxy-2-nitronaphtho[2,1-b]furan (R 7000; MNNF) labelled with 14C on the furan ring and on the methoxy group, were identified by comparison of their chromatographic behaviour and mass spectra with synthetic authentic reference compounds. Analysis of metabolites indicated three metabolic pathways for this compound in vivo, namely, demethylation of the methoxy group, hydroxylation of the aromatic ring and cleavage of the furan ring, followed by the reduction of the nitro group to amine.

Kinetics of metapramine and its demethylated metabolites after single and chronic oral administration in man.

The kinetics of metapramine and two of its demethylated metabolites were determined in six normal subjects after oral administration of a single 150 mg dose on day 1 and 3 X 50 mg dose on day 2-6. This study has shown that three demethylated metabolites are found in plasma beside metapramine. The monodemethylated metabolite I appeared to be the predominant one and the mean area under the plasma concentration curve (AUCo24) was 49% of the metapramine value.

N-dephenylation of CERM 3517 (mociprazine) in beagle dogs. A mass spectrometric determination.

CERM 3517 (mociprazine), a new antiemetic compound, was administered orally at 10 mg/kg twice a day for 4 days to six Beagle dogs in order to identify the major metabolite. Mass spectrometric comparison of this metabolite and a synthesized reference compound (CERM 4082) showed that both had identical structures. The metabolite originated from cleavage of the aromatic moiety.

Simultaneous determination of metapramine and its demethylated metabolites in plasma by gas chromatography-mass spectrometry.

A capillary column gas chromatography--mass fragmentographic method for metapramine and its three major demethylated metabolites is described. Compounds are extracted from plasma using a double-extraction procedure and transformed into N-trifluoroacetyl derivatives. The detection is performed by monitoring specific ions for metapramine and for its metabolites with a mass detector.

New cysteamine (2-chloroethyl)nitrosoureas. Synthesis and preliminary antitumor results.

Three chemical pathways were used for the synthesis of four new N'-(2-chloroethyl)-N-[2-(methylsulfinyl)ethyl]- and N'-(2-chloroethyl)-N-[2-(methylsulfonyl)ethyl]-N- or N'-nitrosoureas. These compounds are plasma metabolites of CNCC, a promising antineoplastic (2-chloroethyl)nitrosourea. Preliminary antitumor evaluation was performed against L1210 leukemia implanted intraperitoneally in mice.

Metabolic disposition of 2-chloroethyl nitrosocarbamoylcystamine in rats.

The disposition and the metabolism of 2-chloroethyl nitrosocarbamoylcystamine (CNCC), a new antitumor agent, has been studied in rats. For this purpose, three separate labeled species of CNCC have been used. The tissue distribution and the elimination of the radioactivity were determined in animals after gavage with a single dose of each labeled species of CNCC (35 mumol/kg).

Pharmacokinetic study of 3H-labelled PAF-acether II. Comparison with 3H-labelled lyso-PAF-acether after intravenous administration in the rabbit and protein binding.

The blood and plasma kinetics of intravenously administered 3H-labelled PAF-acether were determined in seven rabbits. PAF-acether was rapidly distributed and slowly eliminated. Individual variations were very small.