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F M Pasutto

Publications and source records attributed to F M Pasutto.

At least 37 records · Page 2Linked to original sources
PubMed1990

Stereospecific high-performance liquid chromatographic assay of acebutolol in human plasma and urine.

A sensitive high-performance liquid chromatographic technique is described for the separation of R- and S-acebutolol in human plasma and urine. The procedure involves derivatization with the chiral reagent S-(+)-1-(1-naphthyl)ethyl isocyanate. The resulting diastereoisomers are quantified using normal-phase high-performance liquid chromatography with fluorescence detection (220/389 nm). Virtual baseline separation, free from interference, with achieved (resolution factor = 1.45). Excellent linearity (r greater than 0.998) was observed throughout the range 10-500 ng/l and 2-100 mg/l in plasma and urine, respectively. Inter-assay variability was less than 5% for each enantiomer at concentrations of 10 ng/ml. This method is applicable for the determination of the pharmacokinetics, in man, of acebutolol enantiomers in plasma and urine.

Acebutolol↗
PubMed1990

High-performance liquid chromatographic determination of the enantiomers of flecainide in human plasma and urine.

A stereospecific high-performance liquid chromatographic method for the determination of (R,S)-flecainide acetate [(R,S)-N-(2-piperidylmethyl)-2,5-bis-(2,2,2-trifluoroethoxy)benzam ide acetate] in human plasma and urine is described. After addition of the internal standard [IS; (R,S)-N-(2-piperidylmethyl)-2,3-bis(2,2,2-trifluoroethoxy)- benzamide hydrochloride], a single-step extraction of alkalinized samples was performed with distilled diethyl ether. The organic layer was evaporated and the drug and IS were derivatized with 1-[(4-nitrophenyl)sulfonyl]-L-propyl chloride at 80 degrees C for 2 h. The diastereomeric derivatives of flecainide and IS were chromatographed on a C18 reversed-phase column with a mobile phase consisting of acetonitrile: water:triethylamine (45:55:0.2) at a flow rate of 1 mL/min. Flecainide diastereomers were separated with a resolution factor of 1.25 and detected by UV spectroscopy at a wavelength of 280 nm. An excellent linearity was observed between the peak area ratios (flecainide derivatives:IS) and plasma concentrations, and the intra- and interday coefficients of variation were always less than 9.8%. The lowest quantifiable concentration was set at 50 ng/mL for each enantiomer (CV of 4.9 and 4.4%), while the lowest limit of detection (signal:noise, 3:1) was on the order of a few nanograms. The assay was used to study the pharmacokinetics of flecainide enantiomers in a patient receiving (R,S)-flecainide therapy. The steady-state plasma time courses for the enantiomers were found to be parallel, but the difference between (R)- and (S)-flecainide concentrations was significant. The urinary excretion data were consistent with the plasma results. The method is suitable for therapeutic monitoring of flecainide enantiomers and for stereoselective pharmacokinetic studies in humans.

Adult↗
PubMed1990

Synthesis and pharmacological evaluation of acyl derivatives of phenelzine.

Acyl derivatives of phenelzine were required for pharmacological evaluation. Eight mono- and di-acyl derivatives were synthesized and characterized by gas chromatography, mass spectrometry, nuclear magnetic resonance and infrared spectrophotometry. Selective acylation was observed with both acetic anhydride and ethyl chloroformate. In aqueous medium, monoacylation yielded N1-acetyl- and N1-(ethoxy-carbonyl)-phenelzine exclusively, whereas in non-aqueous medium only N2-acetyl and N2-(ethoxycarbonyl) products were obtained. NMR temperature studies were conducted to ascertain the presence of rotational isomers and their ratios. At room temperature, one ethoxy-carbonyl and four phenelzine acetate derivatives were present as mixtures of rotamers. Preliminary evaluations of the MAO-inhibiting properties of acylated phenelzines indicate that a hydrogen atom on the N1-position of phenelzine and its derivatives is essential for activity.

Acylation↗
PubMed1989

Leukotriene D4 and platelet-activating factor-acether antagonists on allergic and arachidonic acid-induced reactions in guinea pig airways.

Arachidonic acid (AA) and ovalbumin (OA) were used to induce contractions of sensitized guinea pig tracheal spiral (indomethacin-pretreated) and lung parenchymal strip preparations. This model was used to examine the properties of three leukotriene (LT) D4 antagonists and a platelet-activating factor (PAF)-acether receptor antagonist. The three LTD4 antagonists, L-649,923, FPL 57231, and LY163443, inhibited AA-induced contractions of indomethacin-pretreated tracheal spirals selectively. The PAF-acether antagonist, L-652,731, did not inhibit AA-induced contractions of either trachea or parenchyma. This confirmed that AA-induced contractions of trachea involved release and activity of LTD4. The LTD4 antagonists and L-652,731 partially inhibited OA-induced contractions of both trachea and parenchyma. When L-649,923 and L-652,731 or FPL 57231 and L-652,731 were combined, an additive inhibitory effect on OA-induced contractions was observed. When LY163443 and L-652,731 were combined, the inhibitory effect was synergistic. This may be due to the additional effect of LY163443 to inhibit phosphodiesterase. Total inhibition of OA-induced contractions was obtainable with relatively low concentrations when a LTD4 and PAF-acether antagonist were combined. These results suggested that LTD4 and PAF-acether may be the two major mediators in our model of allergic bronchospasm. The LTD4 and PAF-acether antagonists had the capacity to decrease baseline tone, even on tissues that were already relaxed with indomethacin, suggesting that LTD4 and PAF-acether may contribute to intrinsic tone in airway smooth muscle.

Animals↗
PubMed1989

Biotransformation of aryl alkylamines by Cunninghamella bainieri.

1. Incubations of phenylethylamine and 11 of its analogues with Cunninghamella bainieri have been performed. 2. Products of all major routes of mammalian metabolism including ring and aliphatic hydroxylation, oxidative deamination, N-oxidation, N-dealkylation, and conjugation were found in extracts of the fungal incubation broths. 3. Metabolism was influenced by the nature and degree of substitution.

Biotransformation↗
PubMed1988

Rapid and sensitive high-performance liquid chromatographic assay of tiaprofenic acid enantiomers in human plasma and urine.

A sensitive stereospecific high-performance liquid chromatographic assay of tiaprofenic acid (TA) enantiomers in human plasma and urine was developed. The biological specimens are acidified, and the drug and internal standard, (+/-)-2-(4-benzoylphenyl)butyric acid, extracted with an isooctane-isopropanol (95:5) mixture (plasma) or chloroform (urine), followed by sequential reaction of the enantiomers with trichloroethyl chloroformate and L-leucinamide. The reactions were complete at ambient temperature in less than 3 min. The diastereoisomers of TA and internal standard were then extracted into chloroform. The organic layer was evaporated, and the reconstituted residue chromatographed at ambient temperature on a C18 reversed-phase column with a mobile phase consisting of 0.06 M monopotassium phosphate-acetonitrile-triethylamine (65:35:0.02) at a flow-rate of 1 ml/min. The TA diastereoisomers were detected at 310 nm, free of interfering peaks, with a resolution factor of 2.1. Within the examined plasma and urine enantiomeric concentration ranges of 0.2-20 and 10-100 mg/l, respectively, an excellent linear relationship was obtained between the peak-area ratios and the corresponding concentrations. The assay was reproducible and sufficiently accurate to be applied to the stereoselective pharmacokinetic analysis of TA enantiomers in plasma and urine following administration of therapeutic doses of the drug.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

Microbial metabolism of phenelzine and pheniprazine.

Phenelzine and pheniprazine were used as substrates for metabolic studies with Cunninghamella echinulata and Mycobacterium smegmatis. Metabolites were identified by means of gas-liquid chromatography and mass spectrometry. 1-Acetyl-2-(2-phenylethyl)-hydrazine and 1-acetyl-2-(1-methyl-2-phenylethyl)hydrazine were the major products of C. echinulata metabolism of phenelzine and pheniprazine, respectively. In addition, M. smegmatis produced a second metabolite from each substrate; these metabolites were unequivocally identified as N-acetylphenylethylamine and N-acetylamphetamine from phenelzine and pheniprazine, respectively.

Amphetamines↗
PubMed1988

Pharmacokinetics of ibuprofen enantiomers in humans following oral administration of tablets with different absorption rates.

Ibuprofen (IB) is a racemic drug and is administered as such. While activity is due mainly to the S enantiomer, pharmacokinetic interpretations, as well as criteria to assess the bioequivalence of IB formulations, are based on measurements of the total (S + R) drug concentrations. IB enantiomers possess different disposition properties mainly as a result of R-to-S isomeric bioinversion. Inversion is maximal during the absorption phase, suggesting, perhaps, involvement of a presystemic process. This concept was evaluated in healthy subjects by crossover administration of four IB tablets having different absorption rates. The plasma concentrations of the individual isomers were measured using a stereospecific gas chromatographic assay. Differences among the products were insignificant with respect to the extent to the absorption. The S:R concentration ratios rose for 4 to 6 hr and then remained relatively unchanged. This observation was consistent with equal terminal t1/2 values for the enantiomers. There were significant differences between the peak times (Tmax) of the products. The S:R ratios of the concentrations at Tmax of S and AUC also differed; significant positive correlations were found between Tmax and the S:R ratios of Cmax. Thus the extent of R-to-S inversion, and hence the potency of a racemic dose of IB, may be absorption rate dependent.

Administration, Oral↗
PubMed1988

Liquid-chromatographic assay of ibuprofen enantiomers in plasma.

This stereospecific "high-performance" liquid-chromatographic (HPLC) assay is suitable for pharmacokinetic studies of ibuprofen (IB). Very efficient extraction of the drug and internal standard, (+/-)-2-(4-benzoylphenyl)butyric acid, from plasma with isooctane/isopropanol (95/5, by vol) is followed by sequential reaction of the enantiomers with ethyl chloroformate and (S)-(-)-1-(1-naphthyl)ethylamine. The reactions take place at ambient temperature in less than 4 min. The naphthylethylamide derivatives of IB enantiomers and internal standard are then extracted into chloroform. After the organic layer is evaporated, the reconstituted residue is chromatographed at ambient temperature on a C18 reversed-phase column with a mobile phase of acetonitrile/water/acetic acid/triethylamine (55/45/0.1/0.02 by vol) at a flow rate of 1 mL/min. The IB diastereoisomers, detected at 232 nm, are free of interfering peaks and have a resolution factor of 2.2. Within the examined enantiomer concentration range of 0.1 to 20 mg/L in plasma, the peak-area ratios varied linearly with the corresponding IB concentrations. We used the assay to study the pharmacokinetics of IB enantiomers in plasma of a subject who took a single 600-mg dose of racemic drug.

Chromatography, High Pressure Liquid↗
PubMed1987

In vivo metabolism of lidocaine in the rat. Isolation of urinary metabolites as pentafluorobenzoyl derivatives and their identification by combined gas chromatography-mass spectrometry.

The metabolism of a large dose (40 mg/kg intraperitoneally) of lidocaine (LIDO) in mature male Sprague-Dawley rats is described. Pentafluorobenzoyl chloride was used to derivatize the hydrolyzed urinary metabolites prior to extraction and analysis as pentafluorobenzoyl-derivatives by combined gas chromatography-mass spectrometry. Total ion and selected ion current (m/z 195; C6F5CO+) traces were recorded and metabolites of LIDO were readily identified. Only one major metabolite, 3-hydroxy-N-(N-ethylglycyl)-2,6-xylidine, was excreted in urine. A new metabolite, 3-hydroxy-N-glycyl-2,6-xylidine was also present in significant amounts, as well as minor quantities of four oxygenated metabolites of N-(N-ethylglycyl)-2,6-xylidine. Other known metabolites of LIDO, including 3-hydroxylidocaine, were excreted in trace quantities. The results suggest that metabolism of LIDO in rats may be age- and/or dose-dependent.

Animals↗
PubMed1987

Simultaneous extraction and quantitation of several bioactive amines in cheese and chocolate.

A method is described for simultaneous extraction and quantitation of the amines 2-phenylethylamine, tele-methylhistamine, histamine, tryptamine, m- and p-tyramine, 3-methoxytyramine, 5-hydroxytryptamine, cadaverine, putrescine, spermidine and spermine. This method is based on extractive derivatization of the amines with a perfluoroacylating agent, pentafluorobenzoyl chloride, under basic aqueous conditions. Analysis was done on a gas chromatograph equipped with an electron-capture detector and a capillary column system. The procedure is relatively rapid and provides derivatives with good chromatographic properties. Its application to analysis of the above amines in cheese and chocolate products is described.

Amines↗
PubMed1987

Acetylation and pentafluorobenzoylation of lidocaine metabolites in aqueous solution and identification of derivatives by combined gas chromatography/mass spectrometry.

Known and possible phenolic and primary and secondary amine metabolites of lidocaine were added to urine from drug-naive rats. These metabolites were derivatized in this aqueous medium by acetylation with acetic anhydride or by pentafluorobenzoylation with pentafluorobenzoyl chloride. The derivatives were simultaneously extracted into an organic solvent. The products were separated by gas chromatography (flame ionization detection for acetates and electron-capture detection for pentafluorobenzoates) and identified by combined gas chromatography/mass spectrometry. Mass spectral fragmentation pathways were readily deduced; diagnostic fragment ions were identified and were valuable for characterization purposes. Structural isomers could be distinguished on the basis of their GC retention times. Extractive derivatization using pentafluorobenzoyl chloride is an attractive analytical procedure for the identification of phenolic and dealkylated metabolites of lidocaine.

Acetylation↗
PubMed1987

Microbiological systems in organic synthesis: preparation of racemic prenalterol utilizing Cunninghamella echinulata.

The fungal microorganism Cunninghamella echinulata was utilized to para-hydroxylate the synthetic substrate (+/-)-1-isopropylamino-3-phenoxy-propan-2-ol (1). The resulting product, (+/-)-1-(4-hydroxyphenoxy)-3-isopropylamino-propan-2-ol, or (+/-)-prenalterol, (2) was formed in greater than 85% yield. Extracts from incubates were derivatized with trifluoroacetic anhydride and the concentrations of 1 and 2 were determined by GC on a fused silica methyl silicone capillary column with nitrogen-phosphorus detection. At substrate concentrations of 100 and 200 mg/L, the biotransformation proceeds with apparent first-order kinetics. With higher concentrations, the kinetics of prenalterol formation and substrate uptake appear to be nonlinear with a Km value of 427.8 micrograms/mL and a Vmax value of 232.3 micrograms/mL/d. This suggests that the biotransformation may proceed through a single-capacity limited pathway. The microbial product was isolated and identified as (+/-)-prenalterol by comparison (mp, IR, MS, 1H NMR) with an authentic specimen.

Biotransformation↗
PubMed1986

Gas chromatographic separation of optically active anti-inflammatory 2-arylpropionic acids using (+)- or (-)-amphetamine as derivatizing reagent.

A method is described for the derivatization of several non-steroidal anti-inflammatory arylalkanoic acids (ibuprofen, ketoprofen, naproxen, fenoprofen, flurbiprofen, pirprofen, cicloprofen, tiaprofenic acid, etodolic acid) with optically active amphetamine. The usefulness of this reagent compared to alpha-methylbenzylamine is described. The enantiomers are separated as diastereoisomers using capillary gas chromatography with nitrogen-phosphorus detection. The procedure is readily applied to the quantification of the enantiomers in urine and plasma samples.

Amphetamine↗
PubMed1986

Pharmacokinetics of the enantiomers of tiaprofenic acid in humans.

A gas chromatographic method was utilized to study stereoselective pharmacokinetics of the nonsteroidal anti-inflammatory drug, tiaprofenic acid (5-benzoyl-alpha-methyl-2-thiopheneacetic acid), in four arthritic patients receiving 200 mg/8 h of the racemic drug. Synovial concentrations of the enantiomers were also measured following administration of single 200-mg doses of the drug to six other patients. In the analytical procedure, racemic tiaprofenic acid was coupled to (S)-(+)-amphetamine and the corresponding diastereoisomeric amide derivatives were resolved. Analysis of serial blood and urine samples at steady state, and single synovial samples, revealed that tiaprofenic acid enantiomers had superimposable plasma concentration-time and urinary excretion-time profiles and equivalent synovial concentrations. These results indicate that, unlike most 2-arylpropionic acid anti-inflammatory drugs, tiaprofenic acid enantiomers do not have different disposition kinetics, and the metabolic chiral inversion of one to the other does not occur or is so slow that the drug is eliminated before significant inversion takes place.

Anti-Inflammatory Agents↗
PubMed1986

Metabolism and disposition of N-(2-cyanoethyl)amphetamine (fenproporex) and amphetamine: study in the rat brain.

N-(2-Cyanoethyl)amphetamine (fenproporex, CE-AM) is a clinically used anorexiant claimed to be devoid of the stimulant properties associated with amphetamine (AM). This claim was inconsistent with preliminary studies conducted in our laboratories which indicated that CE-AM is metabolically dealkylated to AM to a considerable extent in the rat. Concentration-time profiles of CE-AM and its metabolites AM and 4-hydroxyamphetamine (4-OH-AM) in the rat brain were constructed after administration of CE-AM. Analyses of CE-AM, AM, and 4-OH-AM were performed by gas chromatography with electron-capture detection using pentafluorobenzoyl chloride (under aqueous conditions) as the derivatizing reagent. The half-life (t1/2) and the maximum concentration (Cmax) of AM after administration of CE-AM were calculated to be 2.04 and 0.56 times the respective t1/2 and Cmax obtained after an equimolar dose of AM. Significant differences in the profiles of 4-OH-AM were also observed. The Cmax of 4-OH-AM in rat brain after administration of CE-AM was nearly 4 times higher and the tmax (time at which concentration is maximum) 4 times lower than the respective Cmax and tmax values of 4-OH-AM observed after an equimolar dose of AM.

Amphetamine↗