Use of deuterium labelling in mechanistic studies of the metabolic chiral inversion of ibuprofen

Baillie, Thomas A.; Adams, Wade J.; Kaiser, David G.; Olanoff, Lawrence S.; Halstead, Gordon W.; Harpootlian, Harry; Giessen, G. Van

doi:10.1016/0883-2889(88)90270-5

Cited by 32 publications

(56 citation statements)

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“…Ibuprofen is a non-steroidal antiinflammatory drug for which it is reported that unidirectional conversion from (R)-ibuprofen to (S)-ibuprofen takes place in vivo in humans (Baillie et al, 1989;Rudy et al, 1991) rats (Chen et al, 1990;Itoh et al, 1997) and several other animal species (Chen et al, 1991). Itoh et al (1997) measured protein binding of individual ibuprofen enantiomers to rat plasma.…”

Section: Species Dependency On Stereoselective Drug-protein Binding Smentioning

confidence: 98%

Microseparation techniques for the study of the enantioselectivity of drug–plasma protein binding

Escuder-Gilabert

Martínez-Gómez

Villanueva-Camañas

et al. 2008

Biomedical Chromatography

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Stereoselectivity in protein binding can have a significant effect on the pharmacokinetic and pharmacodynamic properties of chiral drugs. The investigation of enantioselectivity of drugs in their binding with human plasma proteins and the identification of the molecular mechanisms involved in the stereodiscrimination by the proteins represent a great challenge for clinical pharmacology. In this review, the separation techniques used for enantioselective protein binding experiments are described and compared. An overview of studies on enantiomer-protein interactions, enantiomer-enantiomer interactions as well as chiral drug-drug interactions, including allosteric effects, is presented. The contribution of individual plasma proteins to the overall enantioselective binding and the animal species variability in drug-plasma protein binding stereoselectivity are reviewed.

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Section: Species Dependency On Stereoselective Drug-protein Binding Smentioning

confidence: 98%

Microseparation techniques for the study of the enantioselectivity of drug–plasma protein binding

Escuder-Gilabert

Martínez-Gómez

Villanueva-Camañas

et al. 2008

Biomedical Chromatography

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“…Compared to previously published assays, sample preparation was simplified without the need of post-derivatization sample clean-up [29], sample volume required for analysis was reduced at least 5-fold [6,25,29], the range of the calibration curve was extended into the three-digit range [23, 25,29], baseline separation of (R)-and (S)-ibuprofen was achieved [20,25] and the sensitivity was increased 2-fold [23- 25,29]. The assay was validated with a LOQ of 50 ng/mL, however, the sensitivity of the assay proved to be significantly higher with a LOD of 1 ng/mL.…”

Section: Discussionmentioning

confidence: 99%

“…Ibuprofen undergoes chiral inversion in vitro [1] and in vivo, during metabolism in rats, mouse, rabbits [2][3][4] and humans [5,6] and shows stereoselective pharmacological effects [7,8] metabolism, pharmacokinetics [9][10][11] and disposition [12,13]. It has been reported also that ibuprofen is extensively bound to proteins in plasma in humans [11,14,15].…”

Section: Introductionmentioning

confidence: 99%

“…The indirect techniques include HPLC using UV [26,27], fluorescence [28,29], and mass spectrometric detection [30][31][32][33]. Gas chromatography-mass spectrometry (GC/ MS) methods have been reported as well [2,6,[34][35][36].…”

Section: Introductionmentioning

confidence: 99%

“…GC/MS methods can be stereoselective, but they use a larger sample size for analysis (i.e., 0.8 mL plasma or 1 mL of serum) [34,6], and their sensitivity is insufficient (i.e., 0.25 µg/mL or LOQ 5 µg/mL) [34,35], or they are not stereoselective [35,36]. Several indirect HPLC/ MS/MS methods were reported for various in vitro [30][31][32] and in vivo [33] analyses of ibuprofen, but these methods are not stereoselective and do not represent significant improvement in comparison to the methodologies reported above.…”

Section: Introductionmentioning

confidence: 99%

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A Validated Enantioselective Assay for the Determination of Ibuprofen in Human Plasma Using Ultra Performance Liquid Chromatography with Tandem Mass Spectrometry (UPLC-MS/MS)

Szeitz¹,

Edginton²,

Peng³

et al. 2010

AJAC

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A modified ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantitation of ibuprofen enantiomers in human plasma. Ibuprofen and flurbiprofen (internal standard) were extracted from human plasma at acidic pH, using a single-step liquid-liquid extraction with methyl-tert-butyl ether. The enantiomers of ibuprofen and flurbiprofen were derivatized to yield the corresponding diastereomers. Chromatographic separation was achieved using a phenyl column with a run time of 20 min. (R)-and (S)-ibuprofen were quantitated at the multiple reaction monitoring (MRM) transition of m/z 360.2  232.1, and (R)-and (S)-flurbiprofen were monitored at the MRM transition of m/z 398.3  270.1. The method was validated for accuracy, precision, linearity, range, limit of quantitation (LOQ), limit of detection (LOD), selectivity, absolute recovery, matrix effect, dilution integrity, and evaluation of carry-over. Accuracy for (R)-ibuprofen ranged between -11.8% and 11.2%, and for (S)-ibuprofen between -8.6% and -0.3%. Precision for (R)-ibuprofen was ≤ 11.2%, and for (S)-ibuprofen ≤ 7.0%. The calibration curves were weighted (1/X 2 , n = 7) and were linear with r 2 for (R)-ibuprofen ≥ 0.988 and for (S)-ibuprofen ≥ 0.990. The range of the method was 50 to 5000 ng/mL with the LOQ of 50 ng/mL, and LOD of 1 ng/mL, for (R)-and (S)-ibuprofen requiring 100 µL of sample. The method was applied successfully to a pharmacokinetic study with the administration of a single oral dose of ibuprofen capsules to human subjects.

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Synthesis, chromatographic resolution and chiroptical properties of carboxyibuprofen stereoisomers: Major metabolites of ibuprofen in man

et al. 1997

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The chromatographic resolution of the four stereoisomers of carboxyibuprofen, a major metabolite of ibuprofen in man, was achieved using a Chiralpak AD chiral stationary phase (CSP) (J.T. Baker, Milton, Keynes, UK). The elution order of the stereoisomers was determined to be 2′S,2R; 2′R,2R; 2′R,2S; 2′S,2S by a combination of stereoselective synthesis of diastereoisomeric mixtures and analysis of the two diastereoisomers isolated from human urine following the administration of (S)‐ibuprofen. The individual stereoisomers were isolated by semipreparative chiral phase chromatography and characterized by circular dichroism spectroscopy. Chirality 9:75–87, 1997. © 1997 Wiley‐Liss, Inc.

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Use of deuterium labelling in mechanistic studies of the metabolic chiral inversion of ibuprofen

Cited by 32 publications

References 0 publications

Microseparation techniques for the study of the enantioselectivity of drug–plasma protein binding

Microseparation techniques for the study of the enantioselectivity of drug–plasma protein binding

A Validated Enantioselective Assay for the Determination of Ibuprofen in Human Plasma Using Ultra Performance Liquid Chromatography with Tandem Mass Spectrometry (UPLC-MS/MS)

Synthesis, chromatographic resolution and chiroptical properties of carboxyibuprofen stereoisomers: Major metabolites of ibuprofen in man

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