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J O Malbica

Publications and source records attributed to J O Malbica.

12 recordsLinked to original sources
PubMed1984

High-performance liquid chromatographic determination of tracazolate and its major metabolite in plasma.

A high-performance liquid chromatographic (HPLC) method is reported that provides for either separate or simultaneous plasma determination of tracazolate and its major metabolite, the free carboxylic acid. Tracazolate is extracted from plasma with hexane and is quantitated by reverse-phase HPLC using an internal standard. The metabolite is extracted in an additional step, methylated, and either quantitated using the same HPLC conditions in a separate determination or combined with the hexane extract for the simultaneous HPLC determination of drug and metabolite. The plasma concentrations of metabolite were as much as 60 times greater than free drug in some animal species, therefore requiring the use of separate determinations for the two compounds. The analyses have limits of reproducible quantitation of 20 ng/mL for tracazolate and 50 ng/mL for the metabolite in plasma. The simultaneous analysis for tracazolate and the metabolite was used to evaluate plasma levels of both compounds versus time and dose. Data generated in conjunction with a toxicology study are reported to demonstrate the applicability of the procedure.

Animals↗
PubMed1977

Electron-capture GLC determination of nanogram to picogram amounts of isosorbide dinitrate.

A GLC method for the determination of plasma isosorbide dinitrate using electron-capture detection is described. The organic nitrates are especially suited for electron-capture detection if the detector temperature is optimized for maximum sensitivity, e.g., 175 degrees. Proper maintenance of the detector and column assures reproducible data in the low nanogram range. The extraction procedure described is simple, efficient, and expedient for processing large numbers of samples. The method was used to study plasma levels in four human volunteers after a single dose of a 5-mg chewable isosorbide dinitrate tablet. Concentration levels of isosorbide dinitrate as low as 0.5 ng/ml of plasma can be measured by this procedure.

Adult↗
PubMed1977

Determination of estrogen receptors in canine mammary tumors.

Dextran-coated charcoal assay with Scatchard plotting was used for the quantitative determination of high-affinity estradiol receptors (ER) in 10 canine mammary tumor cytosols. Mammary tumors diagnosed histopathologically as adenocarcinomas appeared to have a higher incidence of ER than those diagnosed as mixed mammary tumors. These receptors have a high affinity for estradiol with dissociation constants as determined by Scatchard analysis ranging from 1.2 to 2.0 X 10(-11) M. These dissociation constants are similar to those previously reported for the receptor-estradio interaction from target tissues in other species. The specific binding of the receptor for the hormone was diminished in the presence of an antiestrogenic compound. Our data suggest that canine mammary tumors with significant ER levels would respond favorably to antiestrogen therapy. With the demonstration of ER sites in canine mammary adenocarcinomas as presented herein, the potential for chemotherapeutic management appears to be encouraging.

Adenocarcinoma↗
PubMed1975

New and expedient determination of atenolol in biological samples.

A method is described for the GLC determination of atenolol BP in plasma and urine. Extraction is accomplished under dehydrating conditions, and interfering impurities are removed by using an acidified cyclohexane-isopropanol mixture (2:1) and charcoal-treated paper disks. The drug thus isolated appears to react more efficiently with heptafluorobutyric anhydride, increasing the sensitivity of GLC electron-capture analysis. Concentrations as low as 0.02 mug/ml were measured using 0.5-ml aliquots of plasma or 0.1 ml of urine. Amino alcohols such as atenolol may form hydrates or alcoholates, precluding complete derivatization with heptafluorobutyric anhydride.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Quantitative high-performance liquid chromatography determination of ICI 125,211 in plasma.

A rapid, specific and quantitative high-performance liquid chromatography assay procedure is described for the determination of ICI 125, 211, (I), a guanidino-thiazole H2-receptor antagonist, in small samples of animal plasma. A 0.2 mL aliquot of plasma is extracted at pH 9 with ethyl acetate. After reconstitution in mobile phase, the sample is run on a silica column using ultraviolet detection at 280 nm. The procedure utilizes ICI 125, 253, (II), an analogous compound as the internal standard. The assay is linear (r2 = 0.99) and the recovery is 97.6 +/- 6.38% over a concentration range of 0.050-5.00 microgram/mL. Detection of levels as low as 0.025 microgram/mL has been documented in some animal study samples. Typical day-to-day precision is 3-9%, relative, for triplicate determinations of four concentrations in the 0.050-0.500 microgram/mL concentration range. Compound (I) is stable in whole blood for at least two hours at room temperature. Plasma concentrations remain constant for at least 48 hours at room temperature and six months at -5 degrees C. The whole blood/plasma ratio averages 0.97 +/- .073 for dog blood (N = 5). Pharmacokinetic data gathered for two dogs dosed orally with an HPMC-TWEEN 80 suspension of (I) at 40 mg/kg gave elimination half-life values of 4.3 and 7.4 hours. The specificity of the HPLC procedure has been confirmed by mass spectrometry.

Animals↗
PubMedDate not supplied

Tracazolate metabolites in rat tissue.

Tracazolate (4-n-butylamino-1-ethyl-6-methyl-1H-pyrazolo[3,4-b] pyridine-5-carboxylic acid ethyl ester) undergoes extensive biotransformation to lipophilic metabolites following oral dosage to male rats. Twenty-one metabolites were identified in a plasma hexane extract by mass spectrometry. Coadministration of unlabeled tracazolate with its stable carbon-13 isotope expedited the isolation and identification of 11 biotransformation products. The various metabolites resulted from either hydrolysis, oxidation, dealkylation, or conversion of an ethyl group to a vinyl group and also from combinations of these biotransformation reactions. Brain extract contained tracazolate and 12 of the metabolites found in plasma. Extracts of fat contained tracazolate and nine of the plasma metabolites. An uncommon type of metabolite less polar than tracazolate (1-vinyl tracazolate) was isolated by HPLC and identified by mass spectrometry.

Adipose Tissue↗
PubMedDate not supplied

Metabolism of tracazolate. Metabolites in dog and rat urine.

The urinary metabolites of tracazolate [4-n-butylamino-1-ethyl-6-methyl-1H-pyrazolo (3,4-b) pyridine-5-carboxylic acid ethyl ester], an anxiolytic agent, obtained from rats and dogs dosed with 14C-labeled tracazolate have been characterized. No unchanged tracazolate was detected. Fifteen metabolites were identified in dog urine, seven of which had not previously been found in rat blood and tissue. Eleven of these metabolites were also found in rat urine. The metabolites were formed by deesterification to the 5-carboxylic acid; N-deethylation of the pyrazole ring: oxidation at the gamma-position of the n-butylamino side chain; oxidation of the terminal carbon of this side chain; loss of the n-butylamino group; and hydroxylation of the 6-methyl group followed by condensation with the 5-carboxylic acid to form gamma-lactones. The major metabolites in dog urine were the desethyl-desbutyl-deesterified compound, the desbutyl-deesterified compound, and the desbutyl-desethyl-lactone. Loss of the butyl side chain and, also, lactone formation, appeared to occur to a lesser extent in the rat than in the dog.

Animals↗
PubMedDate not supplied

Metabolism, disposition, and pharmacokinetics of tracazolate in rat and dog.

The metabolism, disposition, and pharmacokinetics of tracazolate, (4-butylamino-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester), a novel anxiolytic agent, were studied in rat and dog following single oral and iv doses. Although tracazolate exhibits very good absorption (greater than 80%) in both species, it is extensively metabolized, accounting for low bioavailability. Excretion of 14C was rapid, with the kidney being the major organ of excretion. Tracazolate was not detected in the urine after iv doses even though measurable levels were found in blood, suggesting reabsorption of the compound by the renal tubules. The logarithm of the blood drug concentration vs. time data for both species was best described by a three-compartment open model. Mean t1/2 (beta) for tracazolate in the rat and dog were 14 and 10 hr, respectively. The distribution of radioactivity in rats showed that the concentrations of 14C and 14C-tracazolate were greater in tissues than in blood. Tracazolate was the predominant radioactive compound in brain during the first 6 hr and in fat for 96 hr. The extent and decay of tracazolate in fat strongly suggest that this tissue contributes significantly towards the equilibrium of drug between "deep body compartments" and blood. The major metabolite in blood was de-esterified tracazolate (ICI-US 7773) and in brain the gamma-ketotracazolate (ICI-US 10052).

Animals↗