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Biomedical subjects

E Benfenati

Publications and source records attributed to E Benfenati.

At least 55 records · Page 3Linked to original sources
PubMed1988

Effect of butylated hydroxyanisole added in vitro or administered to rats on N,N-dibutylnitrosamine and N-butyl-N-(4-hydroxybutyl)nitrosamine metabolism by post-mitochondrial supernatant of liver homogenates.

The effect of butylated hydroxyanisole (BHA) on P-450-dependent omega-hydroxylation of N,N-dibutylnitrosamine (NDBA) to N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), and the further oxidation of BBN to N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN) by the alcohol/aldehyde dehydrogenase system was investigated using the post-mitochondrial supernatant of liver homogenates (S9) from acutely and chronically BHA pretreated animals or S9 fractions from untreated rats with BHA added. Acute oral BHA (50 and 250 mg.kg-1) did not change NDBA omega-oxidation, which was reduced by 35% only when the compound was administered 0.5% in the diet for 3 weeks. BCPN formation from BBN was unaffected by acute and chronic BHA pretreatment. In order to verify whether BHA or its metabolite(s) had a direct effect on NDBA and BBN oxidation, the compound was added to S9 fractions from untreated rats at various concentrations. Only when BHA concentrations were equimolar or in a 10-fold molar excess to the substrate concentration, we observed 30-50% inhibition of BBN formation and a reduced BCPN formation (60-80% of control values), from BBN. Thus, only at very high BHA concentrations could we confirm the inhibition of P-450-dependent mixed function oxidase and alcohol dehydrogenase activities involved in the metabolism of NDBA and BBN.

Administration, Oral↗
PubMed1987

1-(o-Methoxyphenyl)piperazine is a metabolite of drugs bearing a methoxyphenylpiperazine side-chain.

Drugs bearing an o-methoxyphenylpiperazine (oOCH3PP) moiety in the side-chain of their molecule may form oOCH3PP during biotransformation in-vivo in the rat. This has been verified by combined gas chromatography-mass spectrometry of urine from rats given orally a series of relatively new o-methoxyphenylpiperazine-substituted derivatives. The metabolite is reported to be biochemically and pharmacologically active and therefore its formation may have pharmacological significance, at least for derivatives undergoing extensive cleavage of the arylpiperazine side-chain.

Animals↗
PubMed1985

High-performance liquid chromatographic assay for the determination of p-(3,3-dimethyl-1-triazeno)benzoic acid in mouse plasma.

A reproducible and sensitive method is described for assaying p-(3,3-dimethyl-1-triazeno)-benzoic acid (pCOOH-DMT) and for identifying the N-desmethyl metabolite, p-(3-methyl-1-triazeno)benzoic acid (pCOOH-MMT) using high-performance liquid chromatography. The method measures concentrations as low as 1.25 nmol/ml of plasma. Extraction efficiency of internal standard or of added triazenes averages 88% and the coefficient of variation of the method is less than 10%. pCOOH-DMT is stable at room temperature at pH 7.4, whereas pCOOH-MMT undergoes rapid decomposition (half-life 6 min). pCOOH-MMT is more stable in an albumin-containing solution or in plasma, but not in boiled 9000 g mouse liver. After 80 min incubation with a 9000 g mouse liver fraction and reduced nicotinamideadenine dinucleotide phosphate, only 24% pCOOH-DMT was metabolized. Plasma pharmacokinetic studies in mice treated with 200 mg/kg intraperitoneally showed that the potassium salt of pCOOH-DMT has a half-life of 67 min.

Animals↗
PubMed1985

A comparison of three methods of soft ionization mass spectrometry of crude phospholipid extracts.

Many different classes of phospholipids were identified from crude extracts of hearts by three soft ionization mass spectrometric techniques: liquid matrix secondary ion mass spectrometry in the negative mode, (-)LSIMS, and in the positive mode, (+)LSIMS, and field desorption. (-)LSIMS and (+)LSIMS are complementary methods. In some cases it was possible to establish the fatty acid and aldehyde composition and position of some phospholipid classes, by the analysis of fragments.

Aldehydes↗
PubMed1985

Horseradish peroxidase/hydrogen peroxide-catalyzed oxidation of VP16-213. Identification of a new metabolite.

VP16 was submitted to oxidation catalyzed by horseradish peroxidase (HRP) and H2O2 in phosphate buffer (pH 7.0). The product of the reaction, which has a high performance liquid chromatographic (HPLC) retention time different from the previously known metabolites of VP16, was identified as 1,2,3,4-tetradehydro-VP16 by 1H-NMR and mass spectrometry (MS) analysis. It was found to result from the loss of four hydrogens and the formation of an aromatic ring (ring C of VP16). This new product retains, in the 4' position of the E ring of VP16, the hydroxy group which is crucial for the antitumoral activity of podophyllotoxin derivatives. The reaction was linear in a wide range of VP16 concentrations and was dependent on the concomitant presence of peroxidase and H2O2.

Acetylation↗
PubMed1985

Metabolic studies of a podophyllotoxin derivative (VP16) in the isolated perfused liver.

The metabolism of VP16 was studied in isolated perfused rat liver. The rate of elimination into the medium and excretion in bile were determined by h.p.l.c. with u.v. detection. With high VP16 concentrations (180 micrograms/ml medium), the elimination half-life of the compound was prolonged markedly (156 v. 45 min for lower doses), the percentage recovered in bile was more than halved and drug accumulation in the hepatic tissue was three times greater. These findings indicate saturation of metabolism and of biliary elimination during high-dose treatment. The presence of glucuronides in the bile of VP16 perfused livers indicates that VP16 undergoes conjugation with glucuronic acid. Formation of picro isomer of VP16 in the liver also occurs.

Animals↗
PubMed1984

Identification of a nitrosamino aldehyde and a nitrosamino acid resulting from beta-oxidation of N-nitrosodiethanolamine.

N-nitrosodiethanolamine is converted to N-(2-hydroxyethyl)-N-(formylmethyl)nitrosamine (EFMN) and N-(2-hydroxyethyl)-N-carboxymethyl) nitrosamine (ECMN) by rat S9 liver preparation as a result of beta-oxidation. The beta-oxidized metabolites were isolated and identified by gas chromatography-mass spectrometry (GC-MS) by comparison with authentic standards. An original gas chromatographic method with thermal energy detection was set up to measure both metabolites quantitatively. Under the experimental conditions described, when NAD+ was used as cofactor, about 1% of N-nitrosodiethanolamine (NDELA) was converted to EFMN and about half of the latter product was in turn converted to ECMN. The beta-nitrosamino aldehyde seems to transfer the nitroso moiety to other amino-compounds, even at physiological pH. The significance of the metabolic formation of EFMN in relation to the carcinogenicity of NDELA is discussed.

Animals↗
PubMed1984

Identification and quantitation of 1-arylpiperazines, metabolites resulting from side-chain cleavage of (4-substituted aryl-1-piperazinyl)alkyl heterocyclic derivatives in rat plasma and brain.

Many drugs contain the arylpiperazine moiety in the side-chain of their molecules. A common metabolic pathway of such drugs is cleavage of the side-chain with the formation of 1-arylpiperazines. This has been verified by combined gas chromatography-mass spectrometry of biological samples from rats given orally a series of heterocyclic derivatives bearing a 4-aryl(phenyl, pyrimidinyl, pyridyl or thiazolyl)-1-piperazinylalkyl moiety (oxypertine, zolertine, millipertine, empiprazole, dapiprazole, antrafenine, piribedil, azaperone). A sensitive and selective electron-capture gas-liquid chromatographic procedure for 1-arylpiperazines in rat plasma and brain is described. The overall recovery from plasma and brain was 70-90%. The limit of detection for substituted (halogenated) phenylpiperazines was 10-25 ng/ml or ng/g and 25-100 ng/ml or ng/g for other derivatives. Preliminary data are reported on the time course of the production and elimination of 1-arylpiperazines after oral administration of representative compounds with the arylpiperazine moiety (oxypertine, azaperone and S-3608).

Animals↗
PubMed1984

Physicochemical and analytical characteristics of amiodarone.

Data are reported on the analytical and physicochemical characteristics of amiodarone, for use in identifying and/or assaying this antiarrhythmic agent. The drug is highly soluble in chloroform and poorly soluble in water. Its acid-base constant (pKa) is 6.56, and its maximal lipid solubility range is from pH 3.5 to 5.5.

Amiodarone↗
PubMed1984

Kinetics of 3-tert-butyl-4-hydroxyanisole (BHA) in man.

High-resolution capillary gas chromatography-mass spectrometry with selective ion monitoring and using deuterated 3-tert-butyl-4-hydroxyanisole (BHA) as an internal standard was used to measure BHA in the plasma and urine of human volunteers after oral administration of 30 or 5 mg of the compound in olive oil. Pharmacokinetic studies showed similar plasma-concentration profiles in subjects treated with either level of BHA. About 20% of the administered dose was excreted as BHA glucuronide in the urine within the first 24 hr.

Administration, Oral↗
PubMed1983

Quantitative analysis of minaprine and some of its metabolites with application to kinetic studies in rats.

A simple and rapid high-performance liquid chromatographic method is described for the quantitative analysis of the psychotropic drug minaprine and three of its metabolites (M1, M3 and M11), including one as yet undetected metabolite (M11) known as a monoamine oxidase type A inhibitor in vitro. After selective extraction all four compounds were separated on a reversed-phase muBondapak C18 column using sodium acetate (0.03 M)-acetonitrile-methanol (88:7:5) (pH 3.3) as the mobile phase. The eluted compounds were detected with a UV detector at 254 nm. The sensitivity of the method is 0.02 microgram per millilitre of body fluid or per gram of tissue for M1 and M11 and 0.05 microgram per minaprine and M3. The method has been applied successfully to the determination of minaprine and the metabolites in plasma and brain and is compared here with an gas-liquid chromatographic method with an electron-capture detector previously developed for the detection of minaprine and M11. M11 was identified in rat urine by gas chromatography-mass spectrometry.

Animals↗
PubMed1983

Identification of an acidic metabolite of N-nitrosodiethanolamine isolated from rat urine.

N-Nitrosodiethanolamine metabolism was studied in order to clarify the mechanism(s) by which this compound elicits its carcinogenic effect. Samples of 24 h urine from rats given a single dose of N-nitrosodiethanolamine were collected. Gas chromatographic thermal energy analyses showed the presence of only one compound containing the nitroso moiety besides N-nitrosodiethanolamine. This compound was identified as the acidic derivative N-(2-hydroxyethyl)-N-carboxymethylnitrosamine by comparison with an authentic standard by means of gas chromatographic mass spectrometric analysis of the trimethylsilyl or pentafluorobenzyl esters. The amount of N-(2-hydroxyethyl)-N-carboxymethylnitrosamine excreted in the 24 h urine was about 6% of the N-nitrosodiethanolamine administered.

Animals↗
PubMed1983

Metabolism of the anticancer agent 1-(4-acetylphenyl)-3,3-dimethyltriazene.

High pressure liquid chromatography was used in combination with mass spectrometry to confirm that the main products of in vitro metabolism of 1-(4-acetylphenyl)-3,3-dimethyltriazene are 1-(4-acetylphenyl-3-methyltriazene and 4-aminoacetophenone. In addition a novel metabolite, 1-[4-(1-hydroxyethyl)-phenyl]-3,3-dimethyltriazene, possessing antitumour activity similar to the parent drug, was identified.

Animals↗
PubMedDate not supplied

Mass spectrometric identification of urinary and plasma metabolites of 2-(6'-carboxyhexyl)-3-n-hexylcyclohexylamine, a new antiaggregating agent.

The compound IBI-P-05006, 2-(6'-carboxyhexyl)-3-n-hexylcyclohexylamine, is an antiaggregating agent under development. IBI-P-05006 is an in vitro inhibitor of platelet aggregation. The biotransformation of this compound has been studied in the dog and rat. We present here a study on the metabolites of IBI-P-05006 found in dog and rat urine, and in dog plasma. Analyses were done by gas chromatography-mass spectrometry. In dog urine 15 metabolites were identified. Some of them were also found in dog plasma and in rat urine. The unmetabolized drug was found only in plasma. 10 different hydroxylated metabolites were characterized. The hydroxyl groups were introduced in the hexyl chain in positions omega-4, omega-3, omega-2, omega-1 and omega.

Animals↗
PubMedDate not supplied

Interpretation of quantitative structure-property and -activity relationships.

The potential utility of data reduction methods (e.g. principal component analysis) for the analysis of matrices assembled from the related properties of large sets of compounds is discussed by reference to results obtained from solvent polarity scales, ongoing work on solubilities and sweetness properties, and proposed general treatments of toxicities and gas chromatographic retention indices.

Chemical Phenomena↗
PubMedDate not supplied

Tuning neural and fuzzy-neural networks for toxicity modeling.

The need for general reliable models for predicting toxicity has led to the use of artificial intelligence. We applied neural and fuzzy-neural networks with the QSAR approach. We underline how the networks have to be tuned on the data sets generally involved in modeling toxicity. This study was conducted on 562 organic compounds in order to establish models for predictive the acute toxicity in fish.

Animals↗
PubMedDate not supplied

Predictive carcinogenicity: a model for aromatic compounds, with nitrogen-containing substituents, based on molecular descriptors using an artificial neural network.

A back-propagation neural network to predict the carcinogenicity of aromatic nitrogen compounds was developed. The inputs were molecular descriptors of different types: electrostatic, topological, quantum-chemical, physicochemical, etc. For the output the index TD50 as introduced by Gold and colleagues was used, giving a continuous numerical parameter expressing carcinogenicity. From the tens of descriptors calculated, principal component analysis enabled us to restrict the number of parameters to be used for the artificial neural network (ANN). We used 104 molecules for the study. An Rcv2 = 0.69 was obtained. After removal of 12 outliers, a new ANN gave an Rcv2 of 0.82.

Carcinogenicity Tests↗