Determination of pentoxifylline and its metabolites in human plasma by high-performance liquid chromatography with solid-phase extraction

Mancinelli, Angelo; Pace, Silvia; Marzo, A; Martelli, E. Arrigoni; Passetti, G. L.

doi:10.1016/0378-4347(92)80509-o

Cited by 30 publications

(25 citation statements)

References 19 publications

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“…Liquid chromatography (LC) with ultraviolet spectrometry detection (UV) has been used for the same purposes (GarnierMoiroux et al, 1987;Musch et al, 1989;Mancinelli et al, 1992;Srinivasu et al, 1999;Chmielewska et al, 2006). Relatively poor chromatographic resolution was reported and required sensitivity was supported through time-consuming sample preparation procedures, involving concentration steps, as liquid-liquid extraction (LLE) or solid-phase extraction (SPE).…”

Section: Introductionmentioning

confidence: 99%

Bioanalysis of pentoxifylline and related metabolites in plasma samples through LC‐MS/MS

Sora¹,

Cristea²,

Albu³

et al. 2009

Biomedical Chromatography

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Analytical aspects related to the assay of pentoxifylline (PTX), lisofylline (M1) and carboxypropyl dimethylxanthine (M5) metabolites are discussed through comparison of two alternative analytical methods based on liquid chromatography separation and atmospheric pressure electrospray ionization tandem mass spectrometry detection. One method is based on a 'pure' reversed-phase liquid chromatography mechanism, while the second one uses the additional polar interactions with embedded amide spacers linking octadecyl moieties to the silicagel surface (C-18 Aqua stationary phase). In both cases, elution is isocratic. Both methods are equally selective and allows separation of unknowns (four species associated to PTX, two species associated to M1) detected through specific mass transitions of the parent compounds and owning respective structural confirmation. Plasma concentration-time patterns of these compounds follow typical metabolic profiles. It has been advanced that in-vivo formation of conjugates of PTX and M1 is possible, such compounds being cleaved back to the parent ones within the ion source. The first method was associated with a sample preparation procedure based on plasma protein precipitation by strong organic acid addition. The second method used protein precipitation by addition of a water miscible organic solvent. Both analytical methods were fully validated and used to assess bioequivalence between a prolonged release generic formulation and the reference product, under multidose and single dose approaches.

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Section: Introductionmentioning

confidence: 99%

Bioanalysis of pentoxifylline and related metabolites in plasma samples through LC‐MS/MS

Sora¹,

Cristea²,

Albu³

et al. 2009

Biomedical Chromatography

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“…A single 400 mg dose of pentoxifylline given to human adults produced average peak plasma concentrations of 1.6 and 2.0 mg/L, respectively, for pentoxifylline and lisofylline, whereas respective elimination half-lives averaged 0.8 and 1.0 h (Smith et al, 1986). Analytical methods using gas chromatography and high-performance liquid chromatography with ultraviolet detection (HPLC-UV) have been developed for the detection of pentoxifylline and its metabolites (Burrows, 1987;Grasela and Rocci, 1987;Mancinelli et al, 1992). In general, however, methods based on these techniques have been limited by poor chromatographic resolution and low sensitivity, requiring complex sample concentration techniques or derivitization of the compounds of interest.…”

Section: Introductionmentioning

confidence: 99%

Use of liquid chromatography-tandem mass spectrometry for the analysis of pentoxifylline and lisofylline in plasma

Kyle

Adcock

Krämer

et al. 2005

Biomed. Chromatogr.

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A method was developed for the quantitation of pentoxifylline [1-(5-oxohexyl)-3,7-dimethylxanthine] and a primary active metabolite, lisofylline [1-(5-hydroxyhexyl)-3,7-dimethylxanthine], using high-performance liquid chromatography (HPLC)-tandem mass spectrometry. This method was developed in order to overcome problems encountered with HPLC-ultraviolet detection. The operating parameters of the electrospray interface (PE SCIEX, TurboIon Spray) and lens voltages of the triple-quadrupole detector (PE SCIEX 365) were optimized in positive ion mode to obtain the best sensitivity of the analytes. Collision-induced dissociation was used to produce fragment ions, and multiple reaction monitoring was used to quantitate pentoxifylline (m/z 279/181) and lisofylline (m/z 263/181). Dichloromethane was used to extract the drug, metabolite, and the internal standard (3-isobutyl-1-methylxanthine) from plasma. A reverse-phase C8(2) 150 x 1.0 mm HPLC column was used to resolve all three compounds in less than 6 min. Calibration curves were generated using peak area and were linear from 1 to 1000 ng/mL (R(2) > 0.99). The small sample volume, ease of extraction, and sensitivity provide advantages over more conventional methods of quantitation.

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“…The drugs tested possess a methyl ketone moiety in their structures which was reduced biocatalytically by alcohol dehydrogenases. The chiral products obtained are important, pharmacologically significant metabolites [17][18][19][20][21][22][23]. For example (R)-hydroxy metabolite of PTX ((R)-OHPTX), known as lisofylline, is a drug candidate that has been under investigation for acute respiratory distress syndrome (ADRS), acute lung injury (ALI), septic shock, and mucositis.…”

Section: Introductionmentioning

confidence: 99%

Alcohol Dehydrogenases as Tools for the Preparation of Enantiopure Metabolites of Drugs with Methyl Alkyl Ketone Moiety

Pękala

2009

Sci. Pharm.

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Three dehydrogenases -(R)-alcohol dehydrogenase from L. kefir, (S)-aromatic alcohol dehydrogenase from T. sp. and (S)-alcohol dehydrogenase from T. brockii -were tested for the preparation of enantiopure hydroxyl metabolites of pentoxifylline (PTX), propentofylline (PPT) and denbufylline (DBF). These metabolites have an important pharmacological significance. The experimental conditions were optimized for biocatalytic reactions. LKADH produced the chiral secondary alcohols: (R)-OHPTX, (R)-OHPPT and (R)-OHDBF, in an antiPrelog's rule configuration. In contrast, TBADH and SAADH also generated chiral secondary alcohols, but according to Prelog's rule, giving (S)-OHPTX, (S)-OHPPT and (S)-OHDBF respectively. All the ADHs tested were characterized by a high enantioselectivity (ees of 99-100%), but the yield of bioconversion was only satisfactory for the reactions performed using LKADH, being in the 96-98% range for PPT and PTX respectively.

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Determination of pentoxifylline and its metabolites in human plasma by high-performance liquid chromatography with solid-phase extraction

Cited by 30 publications

References 19 publications

Bioanalysis of pentoxifylline and related metabolites in plasma samples through LC‐MS/MS

Bioanalysis of pentoxifylline and related metabolites in plasma samples through LC‐MS/MS

Use of liquid chromatography-tandem mass spectrometry for the analysis of pentoxifylline and lisofylline in plasma

Alcohol Dehydrogenases as Tools for the Preparation of Enantiopure Metabolites of Drugs with Methyl Alkyl Ketone Moiety

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