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  • 1
    ISSN: 0899-0042
    Keywords: pargyline N-oxide ; chiral nitrogen centre ; flavin-containing monooxygenase ; chiral stationary phase ; high-performance liquid chromatography ; Chiralcel OD ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The monoamine oxidase inhibitor pargyline (N-benzyl-N-methyl-2-propynylamine) is known to undergo extensive in vitro microsomal N-oxidation, thought to be mediated predominantly by the flavin-containing monooxygenase (FMO) enzyme system. Formation of the pargyline N-oxide (PNO) metabolite creates a chiral nitrogen centre and thus asymmetric oxidation is possible. This study describes a reverse-phase high-performance liquid chromatographic (HPLC) method for the quantitation of PNO and a chiral-phase HPLC method for the determination of the enantiomeric ratio of PNO. In vitro microsomal N-oxidation of pargyline was found to be highly steroselective in a number of species, with the (+)-enantiomer being formed preferentially. This metabolic transformation was stereospecific when purified porcine hepatic FMO was used as the enzyme source. © 1994 Wiley-Liss, Inc.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 0899-0042
    Keywords: cimetidine ; sulfoxidation ; urinary metabolite ; enantiomeric composition of cimetidine sulfoxide ; sequential achiral - chiral high-performance liquid chromatography ; preparative chromatographic resolution ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The individual enantiomers of cimetidine sulfoxide were resolved by preparative chromatography using a Chiralcel OC stationary phase and were characterized by the determination of optical rotation and circular dichroism spectra. Cimetidine sulfoxide was isolated from the urine of two healthy male volunteers following oral administration of cimetidine (400 mg). Urine was collected every 2 h for 12 h postdosing, after which time HPLC analysis indicated negligible recovery of the drug as the sulfoxide. Some 7% of the dose was recovered as cimetidine sulfoxide over this period. The enantiomeric composition of cimetidine sulfoxide was determined by sequential achiral - chiral chromatography using the OC phase. Over the collection period the enantiomeric ratio was found to be constant in all samples at (+/-) of 71 ± 2.5:29 ± 2.5. The enantiomeric composition of cimetidine sulfoxide was also determined in rat urine (24 h) following the administration of cimetidine (30 mg/kg po) to male Wistar rats (n = 7). The enantiomeric ratio in this case was found to be (+/-) 57 ± 2.3:43 ± 2.3. These preliminary data indicate that sulfoxidation of cimetidine is stereoselective with respect to the (+)-enantiomer and that species variation in enantiomeric composition occurs. © 1994 Wiley-Liss, Inc.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 0899-0042
    Keywords: N-ethyl-N-methylaniline N-oxide ; chiral nitrogen centre ; flavin-containing monooxygenase ; stereoselective metabolic N-oxidation ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The prochiral tertiary amine N-ethyl-N-methylaniline (EMA) is known to be stereoselectively N-oxygenated in the presence of hepatic microsomal preparations. This biotransformation is thought to be mediated predominantly by the flavin-containing monooxygenase (FMO) enzyme system. In order to characterise this reaction further, the in vitro metabolism of EMA in the presence of hepatic microsomal preparations derived from a number of laboratory species has been examined. EMA N-oxide formation was stereoselective with respect to the (-)-S-enantiomer in the presence of microsomal preparations from all species examined, with the degree of selectivity decreasing in the order of rabbit 〉 rat ∼ LACA mouse ∼ DBA/2Ha mouse 〉 guinea-pig 〉 dog. The enantiomeric composition of the metabolically derived EMA N-oxide appeared to be determined solely by the differential rate of formation of the two enantiomers as opposed to any differences in affinities for the substrate in its pro-R and pro-S conformations. The use of enzyme inhibitors, activators and inducers indicated that EMA N-oxide formation was predominantly mediated by FMO in the presence of rabbit hepatic microsomes and that these agents did not generally affect the stereochemical outcome of the biotransformation. © 1996 Wiley-Liss, Inc.
    Additional Material: 3 Ill.
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  • 4
    ISSN: 0899-0042
    Keywords: high-performance liquid chromatography ; chiral stationary-phase ; flavin-containing monooxygenase ; N-ethyl-N-methylaniline N-oxide, Chiralcel OD ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The prochiral tertiary amine N-ethyl-N-methylaniline (EMA) is known to be metabolically N-oxygenated in vitro with microsomal preparations. This biotransformation is thought to be mediated predominantly by the flavin-containing monooxygenase (FMO) enzyme system. Microsomal N-oxygenation of EMA is known to be stereoselective and varies between species. In order to further characterise this metabolic transformation, we have examined the in vitro metabolism of EMA using purified porcine hepatic FMO. Following incubation of EMA with purified FMO, EMA N-oxide, the only metabolite detected, was found to be produced stereoselectively [ratio (-)-(S):(+)-(R), ca. 4:1]. The enantiomeric ratio of the N-oxide product did not change markedly with respect to time, enzyme or substrate concentration. Determination of the kinetics of formation of the N-oxide indicated a single affinity for the prochiral substrate with differential rates of formation of the enantiomers. The extent of EMA N-oxide formation was shown to be affected by activators and inhibitors of FMO and pH, but its stereoselectively was unaltered. © 1994 Wiley-Liss, Inc.
    Additional Material: 4 Ill.
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  • 5
    ISSN: 1052-9306
    Keywords: Chemistry ; Analytical Chemistry and Spectroscopy
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Electron impact mass spectral studies on the mono-and di-N-oxides of metyrapone and metyrapol revealed that the technique readily differentiates between the mono-N-oxides of metyrapol, but not of metyrapone. The unequivocal mass spectral differentiation between the isomeric N-oxide metabolites of metyrapone was achieved by the selective and rapid reduction of the keto group in these compounds, with sodium borohydride, to yield the correspoding metyrapol-N-oxides. Chromatographic methods (thin-layer chromatography, gas-liquid chromatography and high-performance liquid chromatography) have been developed for the separation and identification of potential in vitro metabolites of metyrapone. Incubation of metyrapone, under oxidative conditions, with rat or mouse hepatic microsomal preparations, afforded metyrapol (keto reduction) and the isomeric mono-N-oxides of metyrapone. Similar incubation with the hepatic soluble fraction yielded, in addition to metyrapol, an α-pyridone metabolite.
    Additional Material: 8 Ill.
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  • 6
    ISSN: 0306-042X
    Keywords: Chemistry ; Analytical Chemistry and Spectroscopy
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The mass spectral characteristics of the N-oxides of a range of 3-substituted pyridines, and of quinoline and isoquinoline, are described. The molecular ion is the base peak in the majority of cases, provided that thermolysis is minimized when using the direct probe or gas chromatograph inlets. Chromatographic and mass spectral evidence is presented which indicates that biological oxidation of the heteroaromatic nitrogen of 3-substituted pyridines is a route of metabolism in vivo and in vitro.
    Additional Material: 4 Ill.
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  • 7
    ISSN: 0306-042X
    Keywords: Chemistry ; Analytical Chemistry and Spectroscopy
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The electron impact and isobutane and ammonia chemical ionization mass spectral characteristics of the N-oxidation products of a series of 4-substituted-N-ethyl-N-methylanilines are described. The thermolability and the relative non-volatility of N-oxides of this type of tertiary aromatic amine makes their unequivocal identification by gas chromatography and electron impact mass spectrometry difficult. Mass spectral identification is facilitated by employing CI mass spectrometry where, under appropriate conditions, the N-oxides give intense protonated molecular ions. Chromatographic, electron impact and chemical ionization mass spectrometric evidence is presented which shows that these 4-substituted tertiary anilines undergo metabolic N-demethylation, N-de-ethylation and N-oxidation in vitro. The suitability of these tertiary aromatic amines as model substrates for mechanistic studies on C- and N-oxidation is discussed.
    Additional Material: 3 Ill.
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