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Biomedical subjects

M G Horning

Publications and source records attributed to M G Horning.

At least 19 recordsLinked to original sources
PubMed1987

Metabolism of bromobenzene. Analytical chemical and structural problems associated with studies of the metabolism of a model aromatic compound.

Our studies of bromobenzene metabolism have shown that the 3,4-oxide is metabolized to 3- and 4-bromophenol through an extended glutathione pathway. The mechanism of sulfur elimination from a dihydrobromobenzene metabolite is not known, although it is known that the aromatization reaction will occur in a 9000-g supernatant fraction of rat liver. The hepatotoxic and nephrotoxic metabolites of bromobenzene are most likely bromthiocatechols and a bromothiopyrogallol, respectively.

Animals↗
PubMed1987

Analytical methods for the study of urinary thioether metabolites in the rat and guinea pig.

Methods are described for the isolation and identification of three classes of bivalent sulfur metabolites characterized as neutral methylthio ethers, ethyl acetate-soluble acidic thioethers and ethyl acetate-insoluble acidic thioethers from rat and guinea pig urine. After extraction of the metabolites by the ammonium carbonate-ethyl acetate procedure, the individual metabolites are separated by capillary gas chromatography and/or by high-performance liquid chromatography with both mu Bondapak C18 and Porasil columns. Identification of the metabolites is based on gas chromatography-mass spectrometry (electron impact) and on fast atom bombardment mass spectrometry. Interesting species differences in metabolism were observed. The major ethyl acetate-soluble acidic thioethers in rat urine are mercapturic acids. In contrast, in the guinea pig a new pathway involving mercaptopyruvic, mercaptolactic and mercaptoacetic acids is operative. The thioether metabolites of styrene oxide and phenanthrene are described, but the procedures have been applied in studies of several drugs and environmental chemicals in our laboratory.

Animals↗
PubMed1982

Metabolite kinetics: formation of acetaminophen from deuterated and nondeuterated phenacetin and acetanilide on acetaminophen sulfation kinetics in the perfused rat liver preparation.

The role of hepatic intrinsic clearance for metabolite formation from various precursors on subsequent metabolite elimination was was investigated in the once-through perfused rat liver preparation. Two pairs of acetaminophen precursors: [14C] phenacetin-d5 and [3H] phenacetin-do, [14C] acetanilide and [3H] phenacetin were delivered by constant flow (10 ml/min/liver) either by normal or retrograde perfusion to the rat liver preparations. The extents of acetaminophen sulfation were compared within the same preparation. The data showed that the higher the hepatocellular activity (intrinsic clearance) for acetaminophen formation, the greater the extent of subsequent acetaminophen sulfation. The findings were explained on the basis of blood transit time and metabolite "duration time." Because of blood having only a finite transit time in liver, the longer the drug requires for metabolite formation, the less time will remain for metabolite sulfation and the less will be the degree of subsequent sulfation. Conversely, when the drug forms the primary metabolite rapidly, a longer time will remain for the metabolite to be sulfated in liver to result in a greater degree of metabolite sulfation. Finally, the effects of hepatic intrinsic clearances for metabolite formation and zonal distribution of enzyme systems for metabolite formation and elimination in liver are discussed.

Acetaminophen↗
PubMed1980

High-performance liquid chromatographic separation and isolation of quinidine and quinine metabolites in rat urine.

A procedure for the separation and isolation of the urinary metabolites of quinidine and quinine by reversed-phase high-performance liquid chromatography is described. Nine metabolites of quinidine and eight metabolites of quinine were detected in the urine of male Sprague-Dawley rats after a single dose of quinidine or quinine (50 mg kg-1). Following extraction from urine, the metabolites were separated on either an analytical or a semi-preparative reversed-phase column by gradient elution. After isolation and derivatization, the metabolites were analyzed by gas chromatography and gas chromatography--mass spectrometry.

Animals↗
PubMed1980

High-performance liquid chromatographic separation of carbamazepine metabolites excreted in rat urine.

A procedure for the separation and isolation of the urinary metabolites of carbamazepine by reversed-phase high-performance liquid chromatography is described. After extraction from urine, the metabolites were separated on either an analytical or semi-preparative C18 mu Bondapak column by gradient elution with methanol-water-acetic acid. Following derivatization the metabolites isolated by the use of the semi-preparative column were analyzed by gas chromatography and gas chromatography-mass spectrometry.

Animals↗
PubMed1978

Metabolism of biphenyl in the rat.

The metabolism of biphenyl in the rat has been studied by using gas chromatographic and mass spectrometric methods. The free and conjugated urinary metabolites were characterized. Eight new metabolites were isolated: a dihydrodiol and two hydroxydihydrodiols were characteristic for the epoxide--diol pathway. There were two dihydroxybiphenyls, a trihydroxybiphenyl, a trihydroxymethoxybiphenyl and 4,4'-dihydroxy-3-methylthiobiphenyl. The mass spectra of the trimethylsilyl derivatives of the metabolites exhibited characteristic doubly charged and metastable ions.

Animals↗
PubMed1978

Methylthio metabolites of naphthalen excreted by the rat.

Eight methylthio metabolites have been found as urinary products of the metabolism of naphthalene in the rat. One was 1-methylthionaphthalene. A second was a methylthio analog and the dihydrodiol, and a third was naphthalene substituted with one hydroxyl and one methylthio group. Two compounds with common structural elements were found; one of these was prepared by synthesis from anti-1,2:3,4-naphthalene dioxide and one from 1 beta, 2 alpha-dithyroxy-3 alpha, 4 alpha-epoxy-1,2,3,4-tetrahydronaphthalene by reaction with 2-keto-4-methylthiobutyric acid or with methionine. Each of these compounds contained one methythio group and three hydroxyl groups substituted on a tetrahydronaphthalene structure. Two metabolites with two methylthio groups and two hydroxyl substituents on a tetrahydronaphthalene ring were also detected; one of these was prepared by synthesis from the dioxide. The most likely metabolic origin of these methylthio metabolites is through the reaction of epoxides (including the diepoxide) with a nucleophile which may be methyl mercaptan, 2-keto-4-methylthiobutyric acid, or methionine.

Animals↗
PubMed1978

Formation in vivo of deuterated methylthio metabolites of naphthalene from L-methionine (methyl-d--3).

Studies were carried out with deuterated methionine (methyl-d--3) to determine if methylthio metabolites of naphthalene were formed in vivo by reaction with methionine-derived metabolites. Rats were maintained on a methionine-free diet for nine days followed by eight days on the same diet supplemented with L-methionine-d--3 prior to administration of naphthalene. When naphthalene metabolites isolated from urine were characterized by GC and GC-MS procedures, it was found that the incorporation of deuterium into the methylthio metabolites, as well as into a catechol methyl ether, was approximately 40%. These results show that the methyl group was derived from methionine.

Animals↗
PubMed1977

Urinary excretion of phenobarbital in a neonate having withdrawal symptoms.

Utilizing methods of gas chromatography-mass spectrometry-computer systems operated in a chemical ionization mode, metabolites of mephobarbital were demostrated in urines collected from two infants whose mother was treated with mephobarbital during pregnancy. Identification of the major metabolite in one infant was possibe for 22 days after delivery. The urinary half-life of mephobartial was 30 hours and the half-life of phenobarbital was 48 hours. Both infants demonstrated withdrawal symptoms for four to six months and manifested the physical phenotype of infants exposed in utero to anticonvulsant agents.

Adult↗
PubMed1977

Use of saliva in therapeutic drug monitoring.

We measured the concentrations of phenobarbital, phenytoin, primidone, ethosuximide, antipyrine, and caffeine in paired samples of saliva and plasma by gas chromatograph-mass spectrometer-computer (GC/MS/COM) and enzyme immunoassay. Mixed saliva was collected for the antipyrine and caffeine studies, parotid saliva for the phenobarbital, primidone, ethosuximide and phenytoin studies. The saliva/plasma (S/P) ratios (by weight) obtained by GC/MS/COM were: phenobarbital, 0.31-0.37; phenytoin, 0.11; ethosuximide, 1.04; antipyrine, 0.83-0.95; caffeine, 0.55. The S/P ratio obtained by enzyme immunoassay were: phenobarbital, 0.32; phenytoin, 0.12; primidone, 0.85. The concentrations of phenytoin, primidone, ethosuximide and antipyrine in saliva correspond to the free fraction of the drug in plasma. When we analyzed samples containing phenobarbital or phenytoin (plasma or saliva) by both techniques, we found that the enzyme immunoassay values were generally higher than GC/MS/COM values, suggesting that the metabolites as well as the parent drug were measured in the immunoassay.

Antipyrine↗
PubMed1976

Profiles of volatile metabolities in body fluids.

A method for the analysis of volatile metabolites present in plasma, urine, breast milk and amniotic fluid collected from mother-infant pairs has been developed which requires only 100 mul of plasma, 3 ml of urine, 20 mul of breast milk and 500 mul of amniotic fluid. After extraction with diethyl ether, the volatile compounds were absorbed on glass wool in a special concentration tube and subsequently desorbed and transferred to a 100-m nickel capillary column for analysis by gas chromatography and gas chromatography-mass spectrometry. The separations, carried out by temperature programming, were complete in 90 min.

Alcohols↗
PubMed1976

Elimination of antipyrine and benzo[a]pyrene metabolism in cultured human lymphocytes.

A strong correlation was found in a carefully selected homogenous population (n = 57) between antipyrine plasma half-life and the percent induction of aryl hydrocarbon hydroxylase by 3-methylcholanthrene in mitogen-stimulated lymphocytes from the same individual. The correlation coefficient of r = 0.923 indicates that antipyrine and benzo[a]pyrene share one or several common determinants that are responsible for the observed interindividual variation in the oxidation rates of the two compounds. When a heterogenous population (n = 80) was studied, the above correlation was not found (r = 0.425).

Adult↗
PubMed1975

The use of gas chromatographic-mass spectrometric-computer systems in pharmacokinetic studies.

Pharmacokinetic studies involving plasma, urine, breast milk, saliva and liver homogenates have been carried out by selective ion detection with a gas chromatographic-mass spectrometric-computer system operated in the chemical ionization mode. Stable isotope labeled drugs were used as internal standards for quantification. The half-lives, the concentration at zero time, the slope (regression coefficient), the maximum velocity of the reaction and the apparent Michaelis constant of the reaction were determined by regression analysis, and also by graphic means.

Chromatography, Gas↗