PubMed Health⌕ Search

Biomedical subjects

W F Trager

Publications and source records attributed to W F Trager.

At least 91 records · Page 5Linked to original sources
PubMed1980

Simultaneous analysis of phenobarbital and p-hydroxyphenobarbital in biological fluids by GLC-chemical-ionization mass spectrometry.

A sensitive and specific GLC-chemical-ionization mass spectrometric method was developed for the simultaneous assay of phenobarbital (I) and p-hydroxyphenobarbital (II) in biological fluids (urine and plasma) using stable isotope analogs of the compounds as internal standards. After extraction, the compounds were methylated with diazomethane and quantitated by GLC-chemical-ionization mass spectrometry. The detection limit of the method was 0.1 micrograms/ml for both compounds. The intraday precision (RSD) for 0.4-2.4 micrograms/ml was < 2% for I and < 4% for II. The interday precision for 0.55 and 2.11 micrograms/ml of each compound was 5.5 and 2.9% for I and 7.3 and 5.0% for II, respectively. This method has been applied in several pharmacokinetic studies.

Gas Chromatography-Mass Spectrometry↗
PubMed1980

Interaction of secobarbital with warfarin pseudoracemates.

To evaluate the interaction of secobarbital with racemic warfarin or R,S(+/-)-warfarin, S(-)-warfarin was synthesized with 13C-label in the 2-position of the coumarin nucleus and added to 12C-R(+)-warfarin to form a 12C-/13C-warfarin pseudoracemate. Six normal subjects received 1.5 mg/kg of this "cold-labeled" pseudoracemate. It was given with and without a daily oral dose of secobarbital, 100 mg, beginning 7 days before the warfarin and continuing throughout the hypoprothrombinemia. Plasma samples were obtained daily and analyzed for warfarin and for one-stage prothrombin activity. Unchanged warfarin in plasma was fractionated by forward-phase high-pressure liquid chromatography, and enantiomorphic ratios were determined by chemical ionization-mass spectrometry with pentadeuterio-warfarin as the internal standard. There was a reduction of the hypoprothrombinemia of the pseuoracemate during the secobarbital regimen over that on warfarin alone (p < 0.001). There was an increase in plasma clearance of R-warfarin (p < 0.05) and an increase in plasma clearance of S-warfarin (p < 0.003) during the secobarbital regimen over that on warfarin alone. It was concluded that secobarbital diminished the hypoprothrombinemia of pseudoracemic warfarin by increasing plasma clearance of the more hypoprothrombinemic S-warfarin and by increasing plasma clearance of the less hypoprothombinemic R-warfarin.

Absorption↗
PubMed1980

Stereoselective interaction of phenylbutazone with [12C/13C]warfarin pseudoracemates in man.

To evaluate the interaction of phenylbutazone with racemic warfarin or R,S-(+/-)-warfarin in man, S-(-)-warfarin or levowarfarin was synthesized with (13)C label in the 2-position of the coumarin nucleus and added to [(12)C]R(+)-warfarin or dextrowarfarin to form a [(12)C/(13)C]pseudoracemate of warfarin. In six normal human subjects, a single oral dose of this "cold labeled" pseudoracemate, 1.5 mg/kg body weight, was administered with and without a daily dosage of phenylbutazone, 300 mg orally, beginning 3 d before the warfarin dose and continuing throughout the hypoprothrombinemia. Plasma samples were obtained daily and analyzed for warfarin content and for one-stage prothrombin activity. Unchanged warfarin in the plasma was fractionated by normal-phase, high-pressure liquid chromatography, and the enantiomorphic ratios were determined by chemical-ionization mass spectrometry with pentadeuteriowarfarin as the internal standard. A highly significant augmentation of the hypoprothrombinemia of the pseudoracemate occurred during the phenylbutazone regimen (P < 0.001) compared with pseudoracemic warfarin administered alone. There was a highly significant increase in the plasma clearance of dextrowarfarin (P < 0.01) and a significant decrease in the plasma clearance of levowarfarin (P < 0.05) during the phenylbutazone regimen compared with administration of warfarin alone. It was concluded that phenylbutazone augmented the hypoprothrombinemia of pseudoracemic warfarin stereoselectively by inhibiting the metabolic disposition of the more hypoprothrombinemic levowarfarin, yet reduced the plasma levels of pseudoracemic warfarin by greatly augmenting the metabolic disposition of dextrowarfarin.

Adolescent↗
PubMed1978

Anomalous chiroptical properties of warfarin and phenprocoumon.

The configurationally similar enantiomers of warfarin and phenprocoumon are found to exhibit circular dichroism curves which are nearly mirror related in the range of 240-340 nm. This effect is interpreted as being due to spatial similarities of the preferred conformations of opposite configurations of the two drugs in solution. An inherently dissymmetric chromophore (theta approximately 1.2 x 10(5)) is observed at approximately 220 nm for warfarin, the cyclic hemiketal tautomeric forms, and the cyclic methyl ketals.

4-Hydroxycoumarins↗
PubMed1978

Conformations of selected 3-substituted 4-hydroxycoumarins in solution by nuclear magnetic resonance. Warfarin and phenprocoumon.

The chemical shift position of the benzylic proton, Hx, has been found to be diagnostic in indicating the preferred conformations of selected 3-substituted 4-hydroxycoumarins. In general, the nonrigid open-chain compounds, e.g., to open-chain tautomer of warfarin and phenprocoumon, are found to exist in equal populations of the two conformations in which the benzylic proton is in the plane of the coumarin ring and is either cis or trans to the 3,4 double bond. The cyclic compounds, e.g., cyclocumoral, are constrained to two limiting conformations defined as axial2 or trans or intermediate conformations between these limits. Evidence is presented that suggests that the antivitamin K activity of warfarin is due to its open side-chain tautomeric form.

4-Hydroxycoumarins↗
PubMed1978

N-Hydroxyamide metabolites of lidocaine. Synthesis, characterization, quantitation, and mutagenic potential.

Two possible N-hydroxyamide metabolites of lidocaine were synthesized and characterized. A combined technique utilizing chemical-ionization mass spectrometry and stable isotope labeling demonstrated that these potentially carcinogenic N-hydroxyamides were neither present in human urine after oral lidocaine administration nor during intravenous infusion of lidocaine for the treatment of ventricular arrhythmias. However, small amounts of 2,6-dimethylphenylhydroxylamine were detected in the urine of all subjects. Mutagenesis assays using the Ames test showed that neither the N-hydroxyamides nor the N-hydroxyarylamine produced revertant colonies above background levels using the Salmonella tester strain TA-1538.

Animals↗
PubMed1977

Improved non-parametric statistical methods for the estimation of Michaelis-Menten kinetic parameters by the direct linear plot.

The theoretical basis for the direct linear plot [Eisenthal & Cornish-Bowden (1974) Biochem. J. 139, 715-720], a non-parametric statistical method for the analysis of data-fitting the Michaelis-Menten equation, was reinvestigated in order to accommodate additional experimental designs and to provide estimates of precision more directly comparable with those obtained by parametric statistical methods. Methods are given for calculating upper and lower confidence limits for the estimated parameters, for accommodating replicate measurements and for comparing the results of two separate experiments. Factors that influence the proper design of experiments are discussed.

Kinetics↗
PubMed1977

Quantification of lidocaine and several metabolites utilizing chemical-ionization mass spectrometry and stable isotope labeling.

Quantification of the suspected metabolites of lidocaine in humans was carried out using the direct insertion probe and chemicalionization mass spectrometry. Deuterated analogs of the metabolites of lidocaine were added to serial human plasma and urine samples and were used as internal standards following oral administration of 250 mg of lidocaine hydrochloride monohydrate to two male subjects and 202 mg of lidocaine free base to one male subject. The average results after analysis of the 0-24 hr urine samples, before beta-glucuronidase-sulfatase treatment, indicated the presence of seven of the possible metabolites in the following amounts (percent of administered dose based on the free base): lidocaine, 1.95; omega-ethylamino-2,6-dimethylacetanilide, 4.90; omega-amino-2,6-dimethylacetanilide, 0.88; m- and/or p-hydroxylidocaine, 0.73; m- and/or p-hydroxy-omega-ethylamino-2,6-dimethylacetanilide, 0.56; 2,6-dimethylaniline, 0.97; and 4-hydroxy-2,6-dimethylaniline, 63.5. Both N-ethyl- and N,N-diethylglycine were detected in human and Rhesus monkey urine, although quantification was not achieved.

Acetanilides↗
PubMed1977

Structure of warfarin in solution.

Warfarin in solution is shown to consist of three interconverting tautomeric structures, two of which are cyclic diastereomeric hemiketals, while the third and minor component is the open-chain intermediate form. The configurations of all the tautomers as well as the major conformations of the cyclic tautomers are assigned. The assignments are supported by comparison with the chemical shift and coupling constant parameters of structurally fixed model compounds.

Chemical Phenomena↗