The stereo inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs and structurally related compounds by Verticillium lecanii

Thomason,; Rhys‐Williams,; Lloyd, Andrew W.; Hanlon,

doi:10.1046/j.1365-2672.1998.00483.x

Cited by 12 publications

(6 citation statements)

References 21 publications

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“…In contrast, benoxeprofen underwent extensive inversion with a ratio up to 98%. When conincubated with Verticillium lecanii, all profens investigated, including ibuprofen, surprofen, ketoprofen, indoprofen, and flubiprofen, inverted unidirectionally from R to S configuration with the exception of ketoprofen in a reverse direction (Thomason et al, 1998). In addition to different affinities to the involved enzymes, different half-lives of various 2-arylpropionionates may be another important factor responsible for the inversion ratio discrepancy.…”

Section: Metabolic Chiral Inversionmentioning

confidence: 98%

Enantioselective Pharmacokinetics of Ibuprofen and Involved Mechanisms

Hao

Wang²

2005

Drug Metabolism Reviews

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Although dexibuprofen (S-ibuprofen) was marketed in Austria and Switzerland, the racemate at various formulations is still extensively used worldwide, and there are no indications that the racemate will be replaced by the single enantiomer. Thus, elucidation of the characteristics and involved mechanisms of the chiral pharmacokinetics of racemic ibuprofen is of special importance for the understanding of the pharmacological and toxicological consequences, and for prediction of the clinically potential drug interactions and influence of the pathological states. Stereoselective pharmacokinetics and metabolism are common features for chiral nonsteroidal antiinflammatory drugs (NSAIDs) and especially for 2-arylpropionic acid derivatives characterized with a chiral center adjacent to the carboxyl group. Although the enantioselective pharmacokinetic characteristics of different NSAIDs should be treated case by case, they share similar mechanisms underlying the protein binding, metabolism and chiral inversion. Ibuprofen was the most extensively researched drug in terms of chiral characteristics and mechanisms. Therefore, elucidation of the mechanisms derived from research on ibuprofen may provide better understanding and prediction of other chiral drugs. This article attempts to elucidate the chiral pharmacokinetics and involved mechanisms of ibuprofen in comparison with other NSAIDs based on recent developments. Topics on history of ibuprofen, enantioselective analysis method, absorption, protein binding, conventional metabolism, metabolic chiral inversion, gene polymorphism, and biochemical developments were included. It is worth mentioning that some underlying biochemical mechanisms, especially for the metabolic chiral inversion and ethnic differences still remain to be seen. Further research is required to develop human-resourced researching model and to provide more evidence concerning the site of inversion, species variation, CYP450 gene polymorphisms, and biochemical mechanisms.

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Section: Metabolic Chiral Inversionmentioning

confidence: 98%

Enantioselective Pharmacokinetics of Ibuprofen and Involved Mechanisms

Hao

Wang²

2005

Drug Metabolism Reviews

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“…S-(−)-1-(1-Naphthyl) ethylamine has been successfully applied to the enantioseparation of some 2-arylpropionic acid non-steroidal anti-inflammatory drugs and mandelic acid using EDC and HOBT as coupling agents [9]. PGA is an acidic compound possessing a carboxyl group in its structure.…”

Section: Chromatographymentioning

confidence: 99%

Simultaneous determination of mandelic acid enantiomers and phenylglyoxylic acid in urine by high-performance liquid chromatography with precolumn derivatization

Wang¹,

Wang²,

Tang³

et al. 2006

Journal of Chromatography B

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“…41 The disposition of enzymes inverting F could be affected by its 2-methyl group. 42 We were interested whether or not DHF undergoes also chiral inversion in the organism. Therefore, human hepatocytes 2 and 4 were incubated with pure DHF stereoisomers.…”

Section: Discussionmentioning

confidence: 99%

Chiral aspects of metabolism of antiinflammatory drug flobufen in human hepatocytes

et al. 2003

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The metabolism of the nonsteroidal antiinflammatory drug flobufen, 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid, was studied in primary cultures of human hepatocytes prepared by two-step collagenase perfusion of livers from four donors. Racemic flobufen or its individual enantiomers, R-(+)- and S-(-)-flobufen were used as substrates. Aliquots of culture medium were collected during 24-h incubation. The time-dependent disappearance of flobufen enantiomers and the formation of metabolites (stereoisomers of dihydroflobufen (DHF)) in hepatocytes were measured by chiral HPLC. The reduction of flobufen in human hepatocytes was stereoselective ((+)-R-flobufen was preferentially metabolized) and stereospecific ((2R;4S)-DHF and (2S;4S)-DHF stereoisomers were mostly formed). Although the structure of flobufen is different from the profens (2-arylpropionates), flobufen undergoes chiral inversion in human hepatocytes. The inversion of R-(+)-flobufen to S-(-)-flobufen predominates. The individual DHF stereoisomers were incubated in hepatocyte cultures and their biotransformation studied. The unidirectional chiral inversion of (2S;4S)-DHF to (2R;4S)-DHF and (2R;4R)-DHF to (2S;4R)-DHF was observed. Stereoselective oxidation of the DHFs to flobufen was also detected. Thus, flobufen metabolism in primary cultures of human hepatocytes is much more complicated (via chiral inversion and DHF re-oxidation) than was presumed from a preliminary achiral point of view.

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The stereo inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs and structurally related compounds by Verticillium lecanii

Cited by 12 publications

References 21 publications

Enantioselective Pharmacokinetics of Ibuprofen and Involved Mechanisms

Enantioselective Pharmacokinetics of Ibuprofen and Involved Mechanisms

Simultaneous determination of mandelic acid enantiomers and phenylglyoxylic acid in urine by high-performance liquid chromatography with precolumn derivatization

Chiral aspects of metabolism of antiinflammatory drug flobufen in human hepatocytes

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