Excretion stereoselectivity of triticonazole in rat urine and faeces.

The purpose of this study was to study the excretion stereoselectivity of triticonazole enantiomers in rat urine and faeces. Six male Sprague-Dawley (SD) rats were administrated 50 mg/kg rac-triticonazole. Rats urine and faeces were separately and quantitatively collected at the following intervals: 0-3, 3-6, 6-9, 9-12, 12-24, 24-36 and 36-48 h. The faeces samples were homogenized in an aqueous solution containing 0.2% DMSO at the ratio of 1 g: 40 mL. An aliquot of 100 µL rats urine or faeces homogenate was spiked and mixed with 6.0 µL of 1.00 µg/mL flusilazole as an internal standard. The triticonazole enantiomers in urine and faeces were determined by using an HPLC/MS-MS after samples preparation. The excreted amounts of enantiomers in the urine showed a significant difference (P < 0.05) except for 3-6 h. The cumulative excretion rate (Xu0→24) in urine was 26.43 ± 0.08% and 37.58 ± 0.11% for R-(-)- and S-(+)-triticonazole, respectively, indicating high enantioselectivity (P < 0.001). The cumulative excretion rate (Xu0→72) in faeces was 6.93 ± 0.03% and 6.77 ± 0.03% for R-(-)- and S-(+)-triticonazole, respectively, without a difference. The results showed that the total cumulative percentage of triticonazole enantiomers accounted for in urine and faeces was 64.00 ± 0.13% and 13.70 ± 0.32%, the urinary excretion of R-(-)- and S-(+)-triticonazole were significantly different and S-(+)-triticonazole was preferentially excreted. However, the faecal excretion of the enantiomers showed no difference.

Pharmacokinetic Properties of Peramivir After Single and Multiple Intravenous Infusions in Healthy Chinese Volunteers.

BACKGROUND AND OBJECTIVES: Peramivir, an antiviral agent for intravenous administration, is used to treat progressive influenza in patients with serious complications. The present study was designed to determine the pharmacokinetics of single and multiple intravenous infusions of peramivir in healthy Chinese subjects. METHODS: Single (150, 300 and 600 mg) and multiple (600 mg) doses of peramivir were intravenously administered to 12 healthy Chinese subjects. There was a 7-day washout period between dosing periods. Blood samples were collected in heparinized tubes at various times. Plasma peramivir and urine peramivir concentrations were measured using a high-performance liquid chromatography-tandem mass spectrometry method. RESULTS: Following single doses of peramivir (150, 300 and 600 mg), the maximum concentration (C max) values were 12,416 ± 3078, 23,147 ± 3668 and 44,113 ± 3787 µg/L, respectively, and the area under the plasma concentration-time curve (AUC) from 0 h to infinity post-dose (AUC∞) values were 24.68 ± 6.48, 47.33 ± 9.22 and 92.43 ± 12.72 mg·h/L, respectively. C max, AUC from 0 to 36 h (AUC0-36) and AUC∞ of peramivir increased proportionally with the dose, and no trend towards accumulation after multiple doses was observed. About 65 % of the peramivir was excreted unchanged in the urine within the first 24 h. CONCLUSIONS: Peramivir pharmacokinetics were dose proportional with increasing doses, with no accumulation after multiple dosing. Peramivir was generally well tolerated, and no serious adverse events occurred.

Characterization of pentoxyverine metabolites in urine using GC/MS after intoxication with Silomat cough drops.

A nearly two and a half year old boy was hospitalized after showing symptoms of disorientation and hallucination. The parents remembered the child playing with a bottle of Silomat cough drops, so that an intoxication was taken into consideration. After liquid/liquid extraction of a urine sample collected in hospital, the underivatized and the acetylated extracts were analyzed by gas chromatography-mass spectrometry (GC/MS) using electron ionization (EI) as well as chemical ionization (CI). In the urine sample high amounts of pentoxyverine (carbetapentane) and several of its metabolites, e.g., different hydrolyzed, desalkylated and ring-hydroxylated products have been identified. The correlation of the results, the observed symptoms, and the access to the Silomat cough drops reveal an intoxication after ingestion of an unknown amount of the antitussive pentoxyverine. Corresponding EI- and CI-GC/MS spectra are presented characterizing the structure of its metabolites.

High-performance liquid chromatographic method for the determination of eclanamine and its N-desmethyl and N,N-didesmethyl metabolites in urine.

A high-performance liquid chromatographic method has been defined for the determination of eclanamine (free base of eclanamine maleate) and two of its metabolites, N-desmethyleclanamine and N,N-didesmethyleclanamine in urine. The method employs 10-ml urine samples, has a linear range from 5 to 500 ng/ml for the three compounds, and has a detection limit of 0.5 ng/ml for each compound. Sample preparation uses a cyanopropylsilane extraction column with washes of water, acetonitrile-water (30:70, v/v), and acetonitrile, and elution with 2% trifluoroacetic acid in acetonitrile. The eluate is evaporated to dryness, the residue dissolved in 1.0 ml acetonitrile-water (10:90, v/v) and 100 microliter are injected onto a Supelcosil LC-CN column. Eclanamine and its metabolites are eluted with an acetonitrile-water (35:65, v/v) eluent containing 0.01 M triethylamine and adjusted to pH 7.0 with phosphoric acid. The method has been validated by preparing and analyzing a series of fortified urines (range 2-500 ng/ml for each compound) on four separate days. Good linearity, precision, reproducibility, and specificity were obtained. Certification of the analytical method was accomplished by analyzing urine specimens collected from one volunteer administered a single oral dose of 45 mg eclanamine maleate. The data suggest that the metabolites of eclanamine have long elimination half-lives with levels still quantifiable in the 72-96 h collection interval.

Gas chromatographic determination of methylcyclopentadienylmanganesetricarbonyl in biological tissues and fluids.

The procedure described for quantitating methylcyclopentadienylmanganese-tricarbonyl (MMT, a fuel additive) in small samples of biological fluids and tissues is based on extracting the MMT into hexane containing biphenyl as internal standard, followed by gas chromatographic analysis. With flame ionisation detection, as little as 1-2 ppm of MMT in tissue can be determined relatively easily. The method is also applicable to in vitro investigations of MMT metabolism, and it has been used to show that the enzymic oxidation of MMT by rat-liver microsomes is a cytochrome P-450-dependent process.

Plasma level studies of penbutolol after oral dose in man.

Plasma levels of penbutolol (HOE 893d) were determined in eight healthy adult male subjects after oral administration of 50-mg capsules. Fast absorpiton of the drug from the gastrointestinal tract was indicated by the rapid increase in plasma levels during the absorption phase, with a peak time at about 1 hour after dosing in all subjects. After the peak level, plasma concentrations declined biexponentially, with an average half-life of 2.5 and 27 hours for the fast and slow disposition phases, respectively. These values were in good agreement with data previously found for this drug. Cumulative excretion of intact drug in the urine of the eight subjects during 72 hours after dosing was less than 4 per cent, except for one subject who excreted 9.82 per cent of the dose. Large individual variations were found for area under the plasma level curves, disposition rates, and amounts of intact drug excreted in the urine. Significant pharmacologic effects were noted in all eight subjects at the 50-mg dose level, and mild side effects were evident in one half of these subjects. The average drop in blood pressure and pulse rate for all subjects was 26/18 mm Hg and 19 beats per minute, respectively.

Determination of the nonnutritive sweetener sodium cyclopentylsulfamate and three of its metabolites, cyclopentylamine, cyclopentanone, and cyclopentanol, in urine of rats and rabbits.

The nonnutritive sweetener sodium cyclopentylsulfamate was fed to Wistar albino rats and New Zealand White rabbits. Urine was collected for 3 days after feeding, combined, and examined for the metabolites cyclopentylamine, cyclopentanone, and cyclopentanol and for sodium cyclopentylsulfamate was assayed by hydrolysis in acidified dioxane-water and subsequent measurement of the absorbance of the product formed (lambdamax = 490 nm) by the liberated amine with p-benzoquinone. The average conversion to cyclopentylamine, cyclopentanone, and cyclopentanol was 0.103, 0.171, and 0.054% in the rabbit and 0.057, 0.016, and 0.008% in the rat, respectively.

On the metabolism of prostaglandin F 2 in female subjects. Structures of two C 14 metabolites.

PIP: [9 beta-3H] prostaglandin F2alpha was injected intravenously into female subjects and the metabolites appearing in the urine were isolated. The structures of 2 metabolites were determined. These were C14 compounds and were assigned the structures alpha dihydroxy-11-keto(tetranor, omega-dinor)-prosta-1,14-dioic acid and 5 alpha, Palphoc 11-trihydroxy-(tetranor omega-dinor)-prosta-1,14-dioic acid (identified as its gamma lactone). Both these metabolites also occurred in their corresponding delta-lactone forms.^ieng

On the metabolism of prostaglandin F 2 in female subjects. II. Structures of six metabolites.

PIP: In vitro studies of PG (prostaglandin) metabolism have shown that they can be transformed by oxidation of the allylic alcohol group at C-15 catalyzed by a PG-specific dehydrogenase. This report describes isolation and chemical studies of several metabolites of PGF2alpha in female subjects. Chromatography, assay of radioactivity, infrared spectrometry, oxidative ozonolysis, reduction with lithium aluminum hydride and sodium borohydride, and solvents were used to analyze the metabolites. Chromatography graphs, chemical diagrams of the metabolite structures, and mass spectrum graphs present the study data. PGF2alpha is transformed into a variety of compounds in man. The stereochemical features of the metabolites have not been rigorously determined. In fact, the metabolic pathways discussed must be considered tentative. The work does provide a chemical background for more detailed studies of the sequences of the transformations and the properties of the enzymes involved. The study elucidated the structures of 5 previously unrecognized metabolites.^ieng