R-ibuprofenoyl-coenzyme A thioester

evidence_span

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experimental_model

Rat isolated adipocytes and hepatocytes incubated with tritiated glycerol and single enantiomers of fenoprofen

exposure

R or S fenoprofen at concentrations spanning the clinically relevant unbound range

limitations

Tested with fenoprofen rather than ibuprofen, which is recorded on the claim. It shows where the activated R thioester can end up when it is not epimerised.

nutrient_topic

Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. · Ibuprofen

organism

Rat

plain_language

The activated R form can be built into body fat as a fake fatty acid, at concentrations people actually reach.

primary_references

[ibu-p3377800] The stereospecific incorporation of fenoprofen into rat hepatocyte and adipocyte triacylglycerols. (1988). https://pubmed.ncbi.nlm.nih.gov/3377800/ DOI: 10.1016/0006-2952(88)90537-0

tissue_or_cell_type

Adipocytes and hepatocytes

Ibuprofen: the enantiomer that works, the one that was called inactive, the one-way chemistry that turns one into the other, and the targets that are not cyclooxygenase (2026-09-22) · lines 175–186

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat isolated adipocytes and hepatocytes incubated with tritiated glycerol and single enantiomers of fenoprofen · source_derived_draft · unverified_draft

### ibu-r-enantiomer-enters-body-fat In rat isolated adipocytes and hepatocytes incubated with tritiated glycerol there was a high-affinity enzymatic process for synthesis of triacylglycerol containing fenoprofen which was stereospecific for the R enantiomer, with apparent Km values of 1.0 micromolar in adipocytes and 2.8 micromolar in hepatocytes, consistent with stereospecific formation of R-2-arylpropionyl-CoA thioesters at clinically relevant unbound concentrations; a second low-affinity process in hepatocytes occurred at concentrations far above those found in man at usual doses. Condition category: normal nutrient_topic: Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. plain_language: The activated R form can be built into body fat as a fake fatty acid, at concentrations people actually reach. organism: Rat tissue_or_cell_type: Adipocytes and hepatocytes experimental_model: Rat isolated adipocytes and hepatocytes incubated with tritiated glycerol and single enantiomers of fenoprofen limitations: Tested with fenoprofen rather than ibuprofen, which is recorded on the claim. It shows where the activated R thioester can end up when it is not epimerised. exposure: R or S fenoprofen at concentrations spanning the clinically relevant unbound range evidence_span: {"source_cache": "artifacts/ibuprofen-research/3377800.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "facf726355f08978d9f447e3cfbd803611011abed9f95b46970540d246ea11e6", "start_char": 0, "end_char": 962, "text_sha256": "facf726355f08978d9f447e3cfbd803611011abed9f95b46970540d246ea11e6"} [ibu-p3377800] The stereospecific incorporation of fenoprofen into rat hepatocyte and adipocyte triacylglycerols. (1988). https://pubmed.ncbi.nlm.nih.gov/3377800/ DOI: 10.1016/0006-2952(88)90537-0

evidence_span

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experimental_model

Deuterium labelling with stereoselective gas chromatography and mass spectrometry in male Sprague-Dawley rats

exposure

R-ibuprofen and R-ring-2H4;2-2H ibuprofen at 7.5 milligrams per kilogram each, given orally together

limitations

The isotope design pins the chemistry: it shows which hydrogen is lost, that losing it is not rate-limiting, and that the intermediate is symmetrical. A rat study.

nutrient_topic

Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. · Ibuprofen

organism

Rat

plain_language

The molecule loses one hydrogen, passes through a shape with no handedness at all, and can come out either way.

primary_references

[ibu-p1676645] Mechanistic studies on the metabolic chiral inversion of R-ibuprofen in the rat. (1991). https://pubmed.ncbi.nlm.nih.gov/1676645/ DOI: 10.1016/s0090-9556(25)07135-1

tissue_or_cell_type

Plasma and urine

Ibuprofen: the enantiomer that works, the one that was called inactive, the one-way chemistry that turns one into the other, and the targets that are not cyclooxygenase (2026-09-22) · lines 84–95

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Deuterium labelling with stereoselective gas chromatography and mass spectrometry in male Sprague-Dawley rats · source_derived_draft · unverified_draft

### ibu-symmetrical-intermediate Chiral inversion of deuterium-labelled R-ibuprofen in the rat yields S-ibuprofen in a process involving quantitative loss of the deuterium atom originally at C-2, labelling at C-2 introduces no measurable kinetic deuterium isotope effect, and metabolism leads to the appearance of R-ibuprofen molecules labelled with four deuteriums, on which basis the proposed mechanism invokes stereoselective formation of the coenzyme A thioester of R-ibuprofen and its conversion to the corresponding enolate tautomer, affording a symmetrical intermediate through which racemization occurs in vivo. Condition category: normal nutrient_topic: Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. plain_language: The molecule loses one hydrogen, passes through a shape with no handedness at all, and can come out either way. organism: Rat tissue_or_cell_type: Plasma and urine experimental_model: Deuterium labelling with stereoselective gas chromatography and mass spectrometry in male Sprague-Dawley rats limitations: The isotope design pins the chemistry: it shows which hydrogen is lost, that losing it is not rate-limiting, and that the intermediate is symmetrical. A rat study. exposure: R-ibuprofen and R-ring-2H4;2-2H ibuprofen at 7.5 milligrams per kilogram each, given orally together evidence_span: {"source_cache": "artifacts/ibuprofen-research/1676645.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "84a6a246386fa4fee28b69fb088aa21f2bc496addf424bd1c03c64eeaf159543", "start_char": 0, "end_char": 1438, "text_sha256": "84a6a246386fa4fee28b69fb088aa21f2bc496addf424bd1c03c64eeaf159543"} [ibu-p1676645] Mechanistic studies on the metabolic chiral inversion of R-ibuprofen in the rat. (1991). https://pubmed.ncbi.nlm.nih.gov/1676645/ DOI: 10.1016/s0090-9556(25)07135-1

evidence_span

{"source_cache": "artifacts/ibuprofen-research/1680979.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4888135fd1db1817c370825ee8a1435b7654e68af33912093c725fe7041341cc", "start_char": 0, "end_char": 1119, "text_sha256": "4888135fd1db1817c370825ee8a1435b7654e68af33912093c725fe7041341cc"}

experimental_model

Enantioselective high performance liquid chromatography in humans with active subcellular hepatic preparations from rats

exposure

Racemic and single-enantiomer ibuprofen, with R-ibuprofen-CoA applied to subcellular fractions

limitations

Establishes the epimerase step directly on the thioester. The tissue survey is in rat; the human arm is the demonstration that inversion is one-way.

nutrient_topic

Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. · Ibuprofen

organism

Human and rat

plain_language

An enzyme flips the activated form from one hand to the other, mostly in the liver and kidney.

primary_references

[ibu-p1680979] Metabolic inversion of stereoisomeric ibuprofen in man. (1991). https://pubmed.ncbi.nlm.nih.gov/1680979/

tissue_or_cell_type

Liver and kidney

Ibuprofen: the enantiomer that works, the one that was called inactive, the one-way chemistry that turns one into the other, and the targets that are not cyclooxygenase (2026-09-22) · lines 97–108

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Enantioselective high performance liquid chromatography in humans with active subcellular hepatic preparations from rats · source_derived_draft · unverified_draft

### ibu-epimerase-acts-on-the-thioester Ibuprofen epimerization in humans is virtually irreversible from R to S, and 2-arylpropionyl-CoA epimerase readily converts R-ibuprofen-CoA into its S counterpart in active subcellular hepatic preparations, with examination of epimerase activity across tissues indicating that this metabolism occurs mainly in liver and kidney; reduced renal clearance together with metabolic bioactivation from inversion may raise plasma levels of the active species unpredictably. Condition category: normal nutrient_topic: Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. plain_language: An enzyme flips the activated form from one hand to the other, mostly in the liver and kidney. organism: Human and rat tissue_or_cell_type: Liver and kidney experimental_model: Enantioselective high performance liquid chromatography in humans with active subcellular hepatic preparations from rats limitations: Establishes the epimerase step directly on the thioester. The tissue survey is in rat; the human arm is the demonstration that inversion is one-way. exposure: Racemic and single-enantiomer ibuprofen, with R-ibuprofen-CoA applied to subcellular fractions evidence_span: {"source_cache": "artifacts/ibuprofen-research/1680979.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4888135fd1db1817c370825ee8a1435b7654e68af33912093c725fe7041341cc", "start_char": 0, "end_char": 1119, "text_sha256": "4888135fd1db1817c370825ee8a1435b7654e68af33912093c725fe7041341cc"} [ibu-p1680979] Metabolic inversion of stereoisomeric ibuprofen in man. (1991). https://pubmed.ncbi.nlm.nih.gov/1680979/

evidence_span

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experimental_model

Purification and kinetic characterisation of 2-arylpropionyl-CoA epimerase from rat liver cytosol and mitochondria

exposure

2-(4-isobutylphenyl)propionyl-CoA and related thioesters

limitations

Characterises the enzyme as a distinct protein and measures the equilibrium. Purified enzyme, so the equilibrium constant is a property of the epimerase and not of the intact animal.

nutrient_topic

Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. · Ibuprofen

organism

Rat

plain_language

Left to itself the enzyme slightly prefers the R form, which is the opposite of what happens in the body.

primary_references

[ibu-p8381432] Purification and characterization of novel "2-arylpropionyl-CoA epimerases" from rat liver cytosol and mitochondria. (1993). https://pubmed.ncbi.nlm.nih.gov/8381432/ DOI: 10.1016/s0021-9258(18)53720-0

tissue_or_cell_type

Liver cytosol and mitochondria

Ibuprofen: the enantiomer that works, the one that was called inactive, the one-way chemistry that turns one into the other, and the targets that are not cyclooxygenase (2026-09-22) · lines 136–147

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purification and kinetic characterisation of 2-arylpropionyl-CoA epimerase from rat liver cytosol and mitochondria · source_derived_draft · unverified_draft

### ibu-equilibrium-favours-r The purified 2-arylpropionyl-CoA epimerases from rat liver cytosol and mitochondria are monomeric 42 kilodalton proteins distinct from methylmalonyl-CoA epimerase, show no bound cofactors and are unaffected by EDTA or metal ions except copper, and for 2-(4-isobutylphenyl)propionyl-CoA the equilibrium constant was estimated at 1.5 in favour of the R isomer, with evidence that proton exchange is mediated by a two-base mechanism and that an active-site carboxylic residue serves as a general base for proton abstraction. Condition category: normal nutrient_topic: Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. plain_language: Left to itself the enzyme slightly prefers the R form, which is the opposite of what happens in the body. organism: Rat tissue_or_cell_type: Liver cytosol and mitochondria experimental_model: Purification and kinetic characterisation of 2-arylpropionyl-CoA epimerase from rat liver cytosol and mitochondria limitations: Characterises the enzyme as a distinct protein and measures the equilibrium. Purified enzyme, so the equilibrium constant is a property of the epimerase and not of the intact animal. exposure: 2-(4-isobutylphenyl)propionyl-CoA and related thioesters evidence_span: {"source_cache": "artifacts/ibuprofen-research/8381432.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9fab6c9ed036c30f7dbfa01fd8499243d7066dfb510489f189a07ac4811c8ff6", "start_char": 0, "end_char": 1149, "text_sha256": "9fab6c9ed036c30f7dbfa01fd8499243d7066dfb510489f189a07ac4811c8ff6"} [ibu-p8381432] Purification and characterization of novel "2-arylpropionyl-CoA epimerases" from rat liver cytosol and mitochondria. (1993). https://pubmed.ncbi.nlm.nih.gov/8381432/ DOI: 10.1016/s0021-9258(18)53720-0

evidence_span

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experimental_model

Purification of a 42 kilodalton epimerase from rat liver cytosol with polyclonal antibodies and peptide sequencing

exposure

R-enantiomers of 2-arylpropionic acids activated to acyl-CoA thioesters

limitations

States the activation asymmetry explicitly and provides the antibody used for tissue mapping. Peptide sequence homology is suggestive rather than functional evidence.

nutrient_topic

Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. · Ibuprofen

organism

Rat and guinea pig

plain_language

The activating enzyme will only pick up the R hand, and that one fact explains the whole one-way chemistry.

primary_references

[ibu-p8615858] 2-Arylpropionyl-CoA epimerase: partial peptide sequences and tissue localization. (1995). https://pubmed.ncbi.nlm.nih.gov/8615858/ DOI: 10.1016/0006-2952(95)02054-3

tissue_or_cell_type

Liver and other tissues

Ibuprofen: the enantiomer that works, the one that was called inactive, the one-way chemistry that turns one into the other, and the targets that are not cyclooxygenase (2026-09-22) · lines 123–134

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purification of a 42 kilodalton epimerase from rat liver cytosol with polyclonal antibodies and peptide sequencing · source_derived_draft · unverified_draft

### ibu-only-r-is-activated The R enantiomers of 2-arylpropionic acids such as ibuprofen exhibit species- and substrate-dependent metabolic chiral inversion in which only R enantiomers are activated to acyl-CoA thioesters by an acyl-CoA synthetase via an adenylate intermediate, and those thioesters are the substrates for the epimerase responsible for chiral inversion; three internal peptide sequences of the purified 42 kilodalton epimerase showed 50% or more homology with regions of enzymes involved in fatty acid metabolism. Condition category: normal nutrient_topic: Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. plain_language: The activating enzyme will only pick up the R hand, and that one fact explains the whole one-way chemistry. organism: Rat and guinea pig tissue_or_cell_type: Liver and other tissues experimental_model: Purification of a 42 kilodalton epimerase from rat liver cytosol with polyclonal antibodies and peptide sequencing limitations: States the activation asymmetry explicitly and provides the antibody used for tissue mapping. Peptide sequence homology is suggestive rather than functional evidence. exposure: R-enantiomers of 2-arylpropionic acids activated to acyl-CoA thioesters evidence_span: {"source_cache": "artifacts/ibuprofen-research/8615858.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "16cf0cde21de3453912debe1cf25c6191784584aac6596a323e5b5c2944d74a5", "start_char": 0, "end_char": 1153, "text_sha256": "16cf0cde21de3453912debe1cf25c6191784584aac6596a323e5b5c2944d74a5"} [ibu-p8615858] 2-Arylpropionyl-CoA epimerase: partial peptide sequences and tissue localization. (1995). https://pubmed.ncbi.nlm.nih.gov/8615858/ DOI: 10.1016/0006-2952(95)02054-3

evidence_span

{"source_cache": "artifacts/ibuprofen-research/9106621.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2ece633650b8d636b2d0315b6d6486f618f7aae8a585c54558dffe344edf0cf", "start_char": 0, "end_char": 1607, "text_sha256": "d2ece633650b8d636b2d0315b6d6486f618f7aae8a585c54558dffe344edf0cf"}

experimental_model

Molecular cloning and bacterial expression of 2-arylpropionyl-CoA epimerase from a rat liver complementary DNA library

exposure

Expressed epimerase assayed by rate of inversion of R-ibuprofenoyl-CoA

limitations

Identifies the gene and, through its homology, suggests the enzyme is not a drug-metabolising enzyme at all. Sequence homology is an inference about function, not a demonstration.

nutrient_topic

Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. · Ibuprofen

organism

Rat

plain_language

The enzyme that activates this drug looks like an enzyme for handling fats, which is probably its real job.

primary_references

[ibu-p9106621] Molecular cloning and expression of a 2-arylpropionyl-coenzyme A epimerase: a key enzyme in the inversion metabolism of ibuprofen. (1997). https://pubmed.ncbi.nlm.nih.gov/9106621/ DOI: 10.1124/mol.51.4.576

tissue_or_cell_type

Liver

Ibuprofen: the enantiomer that works, the one that was called inactive, the one-way chemistry that turns one into the other, and the targets that are not cyclooxygenase (2026-09-22) · lines 149–160

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Molecular cloning and bacterial expression of 2-arylpropionyl-CoA epimerase from a rat liver complementary DNA library · source_derived_draft · unverified_draft

### ibu-the-enzyme-is-a-lipid-enzyme A complementary DNA clone encoding 2-arylpropionyl-CoA epimerase was isolated from rat liver, expressed in Escherichia coli and confirmed by measuring the rate of inversion of R-ibuprofenoyl-CoA, and significant amino acid sequence similarity was found with carnitine dehydratases from Caenorhabditis elegans at 41% and Escherichia coli at 27%, suggesting that this protein, characterised until then only for its role in drug transformation, has a function in lipid metabolism; the R enantiomer is described as inactive in terms of cyclooxygenase inhibition. Condition category: normal nutrient_topic: Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. plain_language: The enzyme that activates this drug looks like an enzyme for handling fats, which is probably its real job. organism: Rat tissue_or_cell_type: Liver experimental_model: Molecular cloning and bacterial expression of 2-arylpropionyl-CoA epimerase from a rat liver complementary DNA library limitations: Identifies the gene and, through its homology, suggests the enzyme is not a drug-metabolising enzyme at all. Sequence homology is an inference about function, not a demonstration. exposure: Expressed epimerase assayed by rate of inversion of R-ibuprofenoyl-CoA evidence_span: {"source_cache": "artifacts/ibuprofen-research/9106621.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2ece633650b8d636b2d0315b6d6486f618f7aae8a585c54558dffe344edf0cf", "start_char": 0, "end_char": 1607, "text_sha256": "d2ece633650b8d636b2d0315b6d6486f618f7aae8a585c54558dffe344edf0cf"} [ibu-p9106621] Molecular cloning and expression of a 2-arylpropionyl-coenzyme A epimerase: a key enzyme in the inversion metabolism of ibuprofen. (1997). https://pubmed.ncbi.nlm.nih.gov/9106621/ DOI: 10.1124/mol.51.4.576