alpha-Methyldopamine, a key intermediate in the metabolic disposition of 3,4-methylenedioxyamphetamine in vivo in dog and monkey.

Metabolites of 3,4-methylenedioxyamphetamine in the urine of dogs and monkeys were separated by gas-liquid chromatography as their trifluoroacetyl and/or n-butyl ether derivatives and identified by comparison of the chromatographic and mass spectrometric behavior of these derivatives with those of synthetic compounds. The metabolites identified in dog and monkey urine were alpha-methyldopamine, 3-O-methyl-alpha-methyldopamine, and 3,4-dihydroxybenzyl methyl ketone. The monkey urine also contained 3,4-methylenedioxybenzyl methyl ketone and 3,4-methylenedioxybenzoic acid present as a glucuronide and/or sulfate conjugate, whereas the dog urine had 3-methoxy-4-hydroxybenzoic acid present as a conjugate other than glucuronide and sulfate.

Formation of a cyclic derivative of ethacrynic acid with diazomethane.

Samples of ethacrynic acid were treated with methanol-hydrochloric acid or with diazomethane. GLC and mass spectrometric analysis indicated that the methanol-hydrochloric acid reaction gave the expected methyl ester, whereas diazomethane treatment gave a compound containing an additional 14 mass units. Accurate mass measurement and PMR and IR spectra showed that this product was a cyclic derivative of the methyl ester of ethacrynic acid, methyl 4-(2,3-dihydro-4-ethyl-5-furyl)-2,3-dichlorophenoxyacetate.

Simultaneous determination of procainamide and N-acetylprocainamide in plasma by high-performance liquid chromatography.

A sensitive, specific, high-performance liquid chromatographic procedure is described for the simultaneous determination of procainamide and its metabolite, N-acetylprocainamide, in plasma. Basic plasma (2.0 ml), containing pheniramine maleate as an internal standard, is partitioned with methylene dichloride.

The bioavailability of commercial metronidazole formulations.

A bioavailability study of eight commercial pharmaceutically equivalent tablet formulations and a solution of metronidazole was conducted in groups of ten subjects with single oral 250 mg doses. Although the solution gave significantly lower extents of bioavailability, the commercial tablets were not significantly different from the (innovator) reference product. The slow rate of absorption for one formulation (F) was observed to be associated with long dissolution time.

GLC determination of plasma concentrations of gamma-oxo metabolite of phenylbutazone.

A quantitative method for the gamma-oxo metabolite of phenylbutazone from plasma is described. The procedure involved an ethylene dichloride extraction of acidified plasma to which an internal standard, acenocoumarol, had been added. The extracted gamma-oxo metabolite and the internal standard were methylated and analyzed by GLC.

Identification of urinary catechol and methylated catechol metabolites of phenytoin in humans, monkeys, and dogs by GLC and GLC-mass spectrometry.

A catechol metabolite, 5-(3,4-dihydroxyphenyl)-5-phenylhydantoin, and a methylated catechol metabolite, 5-(3-methoxy-4-hydroxyphenyl)-5-phenylhydantoin, were identified as urinary metabolites in humans, monkeys, and dogs following the administration of phenytoin. These metabolites were separated from each other and from other known metabolites of phenytoin as n-butyl derivatives by GLC and positively identified by combined GLC-mass spectrometry.

The metabolism of p-methoxyamphetamine in dog and monkey. O-demethylation as a major route.

p-Hydroxyamphetamine (PHA) and p-hydroxybenzoic acid (PHBA) have been isolated by gas-liquid chromatography (GC) as urinary metabolites of p-methoxyamphetamine (PMA) in dogs and rhesus monkeys. The amounts of PMA excreted unchanged in the total 24-hr urine samples in dogs and monkeys were 26% and 3%, respectively, of the total administered doses. The amounts of the pharmacologically active metabolite PHA excreted in 24-hr urine samples were 13% in the dog and 44% in the monkey.

High performance liquid chromatographic and mass spectrometric identification of dimethylxanthine metabolites of caffeine in human plasma.

High performance liquid chromatography and mass spectrometry were used to isolate and identify theophylline, theobromine and 1,7-dimethylxanthine (paraxanthine) in plasma of human volunteers following administration of 300 mg caffeine to methylxanthine-free volunteers. Plasma from these subjects was extracted and the dimethylxanthines were separated from each other and caffeine by high performance liquid chromatography. The effluents at the chromatographic peaks corresponding to the dimethylxanthine metabolites were collected, rechromatographed in a second system and the dried residues were subjected to mass spectrometry.

GLC determination of plasma acenocoumarol levels.

A method for the quantitative estimation of acenocoumarol in plasma is described. Plasma containing acenocoumarol, to which a known amount of gamma-oxo derivative of phenylbutazone is added as an internal standard, is acidified and extracted with ethylene dichloride. The drug and the internal standard are then back-extracted into alkali, which, in turn, is acidified and reextracted with ethylene dichloride.

Identification of 3-O-methyl-alpha-methyldopamine as a urinary metabolite of 3,4-methylenedioxyamphetamine in dog and monkey.

3-O-Methyl-alpha-methyldopamine has been separated by gas-liquid chromatography (GC) as a metabolite of MDA in the urine of dog and monkey. The metabolite was identified as its mono- and di-trifluoroacetyl derivatives by comparison of their GC and GC-mass spectral properties with those of synthetic compounds. The amount of metabolite increased on hydrolyzing the urine from dosed dogs and monkeys with a preparation containing beta-glucuronidase and sulfatase.

Metabolism of methoxyphenamine in man and in monkey.

Metabolites of methoxyphenamine in the urine of human subjects and monkeys were separated by gas-liquid chromatography and identified by comparison of their chromatographic and mass spectrometric behavior with those of synthetic compounds. Aromatic O-demethylation, aromatic ring hydroxylation (both followed by glucuronide conjugation), and N-demethylation were shown to occur in man as well as in monkey. In man these were the principal metabolites, whereas in the monkey three additional unidentified major metabolites were formed.

Sensitive GLC procedure simultaneous determination of phenytoin and its major metabolite from plasma following single doses of phenytoin.

An improved GLC procedure was developed for the simultaneous determination of phenytoin and its metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin, in plasma and urine following enzyme hydrolysis. After extraction, the drug, the metabolite, and the internal standard, 5-(p-methylphenyl)-5-phenylhydantoin, are measured by GLC with flame-ionization detection as their respective methyl derivatives following flash-heater methylation with trimethylanilinium hydroxide. The drug and metabolite give well-resolved symmetrical peaks on a phenyl methyl silicone column, and the method has a sensitivity of 150 ng/ml of phenytoin and 125 ng/ml of the metabolite.

Gas chromatographic and mass spectrometric analysis of the products of methylation of sulfonylurea drugs.

Gas chromatographic analysis of the products of reaction of diazomethane with tolbutamide and chlorpropamide indicates the formation of three compounds in both cases. As expected, N-methylation (at sulfonamide nitrogen) is the predominant reaction; minor amounts of O-methylated product are also observed. The third product in both cases is the N-methylsulfonamide formed by decomposition of the N-methylated sulfonylurea during gas chromatography.

GLC determination of plasma levels of intact chlorpropamide or tolbutamide.

A GLC procedure was developed for the quantitative estimation of intact chlorpropamide and tolbutamide concentrations in plasma; the drugs are used as mutual internal standards. After extraction of plasma containing the drug and internal standard with toluene, the dried residue is treated with ethereal diazomethane to form the methyl derivatives of tolbutamide and chlorpropamide. Aliquots of the ethereal solution are injected into a gas chromatograph equipped with a glass-lined injection port and glass column packed with a phenyl methyl silicone fluid (OV-25) on Chromosorb W, which facilitates the intact determination of the methyl derivatives of the drugs.

GLC determination of plasma concentrations of phenprocoumon.

A GLC method for the quantitative estimation of phenprocoumon from plasma is described. Plasma containing phenprocoumon, to which a known amount of phenytoin is added as the internal standard, is acidified and extracted with ethylene dichloride. The drug and the internal standard are then back-extracted into alkali, which is acidified and reextracted with ethylene dichloride.

GLC identification and determination of 3,4-methylenedioxyamphetamine (MDA) from plasma and urine.

A GLC method for qualitative and quantitative determination of 3,4-methylenedioxyamphetamine in biological fluids is described. After extraction of the drug and the internal standard, 4-methoxyamphetamine, from plasma and urine, the solvent is evaporated and the residue is mixed with 20 mul of freshly distilled ether. Aliquots (1-2 mul) then are injected into the gas chromatograph.