Use of chiral liquid chromatography for the evaluation of stereospecificity in the carbonyl reduction of potential benzo[c]fluorene antineoplastics benfluron and dimefluron in various species

Kučera, Radim; Nobilis, Milan; Skálová, Lenka; Szotáková, Barbora; Cisar, P.; Jira, Thomas; Klimeš, Jiřı́; Wsól, Vladimı́r

doi:10.1016/j.jpba.2004.10.005

Cited by 7 publications

(6 citation statements)

References 23 publications

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“…Based on the fragmentation pattern, the glucuronidation is not placed on the secondary amino group but on the hydroxyl formed by the carbonyl reduction. The carbonyl reduction results in the formation of a chiral carbon atom for reduced DMF and BNF . The coelution of both enantiomers is observed in the case of our separation in a non‐chiral environment.…”

Section: Resultsmentioning

confidence: 69%

“…Enantiomers of chiral drugs and their phase I and II metabolites can be separated on chiral columns . Although the parent drug may not exhibit chirality, the chiral carbon atom can be formed by metabolic reactions, e.g., reduction of a carbonyl group by an enzyme from the aldo‐keto reductase family in the case of flubendazol, pentoxifylline or benzo[ c ]fluorene drugs …”

mentioning

confidence: 99%

“…The biotransformation of benfluron and dimefluron in experimental animals has been studied by various methods using the comparison of chromatographic and spectral properties of the parent drug and several synthesized metabolites, but no information about the formation of phase II metabolites (except one glucuronide) has been reported. Most previous works describe only UV spectra of phase I metabolites and their comparison with synthetic standards . Two articles only contain some MS data.…”

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confidence: 99%

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Identification of phase I and phase II metabolites of benfluron and dimefluron in rat urine using high‐performance liquid chromatography/tandem mass spectrometry

Jirásko

Holčapek

Nobilis

2011

Rapid Comm Mass Spectrometry

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Biotransformation products of two potential antineoplastic agents, benfluron and dimefluron, are characterized using our integrated approach based on the combination of high-performance liquid chromatography (HPLC) separation of phase I and phase II metabolites followed by photodiode-array UV detection and electrospray ionization tandem mass spectrometry (MS/MS). High mass accuracy measurement allows confirmation of an elemental composition and metabolic reactions according to exact mass defects. The combination of different HPLC/MS/MS scans, such as reconstructed ion current chromatograms, constant neutral loss chromatograms or exact mass filtration, helps the unambiguous detection of low abundance metabolites. The arene oxidation, N-oxidation, N-demethylation, O-demethylation, carbonyl reduction, glucuronidation and sulfation are typical mechanisms of the metabolite formation. The interpretation of their tandem mass spectra enables the distinction of demethylation position (N- vs. O-) as well as to differentiate N-oxidation from arene oxidation for both phase I and phase II metabolites. Two metabolic pathways are rather unusual for rat samples, i.e., glucosylation and double glucuronidation. The formation of metabolites that lead to a significant change in the chromophoric system of studied compounds, such as the reduction of carbonyl group in 7H-benzo[c]fluorene-7-one chromophore, is reflected in their UV spectra, which provides valuable complementary information to MS/MS data.

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Section: Resultsmentioning

confidence: 69%

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confidence: 99%

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confidence: 99%

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Identification of phase I and phase II metabolites of benfluron and dimefluron in rat urine using high‐performance liquid chromatography/tandem mass spectrometry

Jirásko

Holčapek

Nobilis

2011

Rapid Comm Mass Spectrometry

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“…[8] No information about the in vivo metabolism of MOP in sheep is available so far, although detailed knowledge of drug metabolism in target species is important for safe and effective therapy including the disclosure of drug-drug interaction. [12,13] The combination of ultra high-performance liquid chromatography (UHPLC) and quadrupole-time-of-flight analyzer (QqTOF) mass spectrometry is very powerful strategy [14] due to the use of selected tandem mass spectrometry (MS/MS) scans, [13,[15][16][17] accurate mass measurements [13,15] and software dedicated to the metabolite prediction or detection. [9] The resistance of nematodes to MOP has not been observed yet, but the gradual development of strains with decreased sensitivity to MOP is highly probable during the next few years.…”

Section: Introductionmentioning

confidence: 99%

Metabolic pathways of anthelmintic drug monepantel in sheep and in its parasite (Haemonchus contortus)

Stuchlíková

Jirásko

Vokřál

et al. 2014

Drug Testing and Analysis

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Monepantel (MOP) is a new anthelmintic drug intended for the treatment and control of gastrointestinal roundworms (nematodes) infection and associated disease in sheep. The aim of our study was to find out metabolic pathways of MOP in sheep in vivo and in its parasite Haemonchus contortus ex vivo. MOP biotransformation in two H. contortus strains with different sensitivity to anthelmintics was also compared. Ultra high-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) technique is used for the identification of MOP metabolites in ovine urine, faeces, and nematodes. MOP biotransformation study in sheep in vivo led to the identification of 13 MOP metabolites; 7 of them have not been described previously in in vitro study. The study of MOP biotransformation in H. contorus ex vivo reveals four MOP metabolites. The nitrile hydrolysis as a new biotransformation pathway in helminths ex vivo is reported here for the first time. Unlike sheep, H. contorus nematodes are not able to metabolize MOP via phase II biotransformation. Nematodes of resistant White river (WR) strain form more types of MOP metabolites than nematodes of sensitive inbred susceptible Edinburgh (ISE) strain. Based on obtained results, schemes of metabolic pathways of MOP in sheep and nematodes are proposed.

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“…The present work describes comparative study of TLC-densitometric method using different cyclodextrin derivatives as chiral selector and different types of TLC-plates at different temperatures. Many chromatographic and electro-chemical methods have been developed for the analysis of enantiomers [5][6][7][8][9]. Among the chromatographic methods so far developed, highperformance liquid chromatographic (LC) methods based on chiral stationary phases, and capillary electro-phoresis are widely employed for the assay of drug isomers in pharmaceutical formulations and biological fluids [10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Development and Validation of TLC-Densitometric Method for Resolution and Determination of Enantiomeric Purity of Ropivacaine, Using Different Cyclodextrins as Chiral Selector

Taha

2007

CPA

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A novel economic procedure for stereoselective separation and determination of R(+) -and S(-)-ropivacaine was described using different thin layer chromatographic plates and different cyclodextrins at different temperatures. The spots were detected either with iodine vapors or UV lamp 254nm, followed by densitometric measurements at 262nm. Comparative study was achieved using different cyclodextrins namely, hydroxypropyl--cyclodextrin (HP--CD), methyl--cyclodextrin (M--CD), and Dimethyl--Cyclodextrin (DM--CD) as chiral selectors. The mobile phase enabling successful resolution of (±) ropivacaine was acetonitrile: water (17:3 v/v) containing 1mM of DM--CD at ambient temperature 25±2 0 C. All variables affecting the resolution, such as concentration of different chiral selectors, temperature, and pH were investigated and the conditions were optimized. The procedure provided a linear response over the concentration range of 1.25 -35 μg/spot for determination of R (+)-and S-(-)enantiomers (r = 0.9998, n = 8), (r = 0.9998, n = 6) with acceptable precision (% RSD <1.5) and accuracy (% RE= -1.18 to 2.00). Limits of detection and quantification were found to be 0.29μg/spot and 0.96 μg/spot for -(R) and 0.26μg/spot and 0.86μg/spot for -(S) respectively. The developed method was validated and proved to be robust. Ropivacaine sample solution was found to be stable for one weak in methanol. The proposed method was found to be selective and accurate for identification and quantitative determination of enantiomeric purity of ropivacaine in bulk powder and pharmaceutical dosage form.

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Use of chiral liquid chromatography for the evaluation of stereospecificity in the carbonyl reduction of potential benzo[c]fluorene antineoplastics benfluron and dimefluron in various species

Cited by 7 publications

References 23 publications

Identification of phase I and phase II metabolites of benfluron and dimefluron in rat urine using high‐performance liquid chromatography/tandem mass spectrometry

Identification of phase I and phase II metabolites of benfluron and dimefluron in rat urine using high‐performance liquid chromatography/tandem mass spectrometry

Metabolic pathways of anthelmintic drug monepantel in sheep and in its parasite (Haemonchus contortus)

Development and Validation of TLC-Densitometric Method for Resolution and Determination of Enantiomeric Purity of Ropivacaine, Using Different Cyclodextrins as Chiral Selector

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