Metabolic chiral inversion of a 2-arylpropionic acid

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/ibuprofen-research/18988084.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "49f5377220f47f04a74dc5e1cd5408a0b175eafbf602e536e57d80a9e8eb1f3a", "start_char": 0, "end_char": 1381, "text_sha256": "49f5377220f47f04a74dc5e1cd5408a0b175eafbf602e536e57d80a9e8eb1f3a"}

experimental_model

Freshly isolated hepatocytes from control rats and rats with adjuvant-induced arthritis

exposure

S- or R-ibuprofen incubated with hepatocytes, with and without serum, and with triacsin C

limitations

Tests whether the disease being treated changes the handling of the drug. Isolated hepatocytes, and the serum arm shows the effect disappears when serum is added back.

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 inflammation the drug is prescribed for slows down the step that makes the drug active.

primary_references

[ibu-p18988084] Impaired intrinsic chiral inversion activity of ibuprofen in rats with adjuvant-induced arthritis. (2008). https://pubmed.ncbi.nlm.nih.gov/18988084/ DOI: 10.1080/00498250802483768

tissue_or_cell_type

Hepatocytes

trigger_kind

machinery_impairment Imported condition classification; unverified.

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 162–173

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Freshly isolated hepatocytes from control rats and rats with adjuvant-induced arthritis · source_derived_draft · unverified_draft

### ibu-arthritis-slows-inversion In hepatocytes isolated from rats with adjuvant-induced arthritis the chiral inversion rate constant of R- to S-ibuprofen and the metabolic rate constants of both enantiomers were significantly decreased to about 64 to 80% of control values, while adding serum from each group abolished the difference; adjuvant-induced arthritis decreased messenger RNA levels of acyl-coenzyme A synthetase isoforms but not of 2-arylpropionyl-CoA epimerase, and chiral inversion was inhibited by triacsin C, a specific inhibitor of acyl-CoA synthetase 1. Condition category: machinery_impairment 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 inflammation the drug is prescribed for slows down the step that makes the drug active. organism: Rat tissue_or_cell_type: Hepatocytes experimental_model: Freshly isolated hepatocytes from control rats and rats with adjuvant-induced arthritis limitations: Tests whether the disease being treated changes the handling of the drug. Isolated hepatocytes, and the serum arm shows the effect disappears when serum is added back. exposure: S- or R-ibuprofen incubated with hepatocytes, with and without serum, and with triacsin C evidence_span: {"source_cache": "artifacts/ibuprofen-research/18988084.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "49f5377220f47f04a74dc5e1cd5408a0b175eafbf602e536e57d80a9e8eb1f3a", "start_char": 0, "end_char": 1381, "text_sha256": "49f5377220f47f04a74dc5e1cd5408a0b175eafbf602e536e57d80a9e8eb1f3a"} [ibu-p18988084] Impaired intrinsic chiral inversion activity of ibuprofen in rats with adjuvant-induced arthritis. (2008). https://pubmed.ncbi.nlm.nih.gov/18988084/ DOI: 10.1080/00498250802483768

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"}

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

{"source_cache": "artifacts/ibuprofen-research/1859831.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "39dd843ee06ac569e1f2a3af9af6af1639e06694a0f8dcd280065c686bd9902f", "start_char": 0, "end_char": 2138, "text_sha256": "39dd843ee06ac569e1f2a3af9af6af1639e06694a0f8dcd280065c686bd9902f"}

experimental_model

Comparative in vivo studies across mammalian species with in vitro epimerization of chemically synthesised ibuprofen-CoA thioester

exposure

Synthetic R- and S-ibuprofen-CoA thioesters applied to tissue homogenates, with and without cofactors

limitations

The decisive control is the failure: homogenates could not invert free R-ibuprofen even with all cofactors, which locates the species difference in the activation step rather than in the epimerase.

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, guinea pig and human

plain_language

The one-way traffic is set by which enantiomer gets activated, not by the enzyme that does the flipping.

primary_references

[ibu-p1859831] Metabolic stereoisomeric inversion of ibuprofen in mammals. (1991). https://pubmed.ncbi.nlm.nih.gov/1859831/ DOI: 10.1016/0167-4838(91)90164-u

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 110–121

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Comparative in vivo studies across mammalian species with in vitro epimerization of chemically synthesised ibuprofen-CoA thioester · source_derived_draft · unverified_draft

### ibu-the-synthetase-sets-direction Liver and kidney homogenates failed to invert R-ibuprofen directly even in the presence of all necessary cofactors, presumably from lack of enzymatic acyl-CoA synthesis, while the 2-arylpropionyl-CoA epimerase catalysed the transformation from either direction with high turnover and with greater catalytic efficiency for S-ibuprofen-CoA epimerization than for the R counterpart, so the acyl-CoA formation step assumes a pivotal role in controlling stereoselectivity and efficiency, and as the responsible synthetases differ between species the outcome varies: in guinea pigs the biotransformation proceeds in both directions with nearly equal efficiency whereas in humans it is virtually unidirectional and slow. 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 one-way traffic is set by which enantiomer gets activated, not by the enzyme that does the flipping. organism: Rat, guinea pig and human tissue_or_cell_type: Liver and kidney experimental_model: Comparative in vivo studies across mammalian species with in vitro epimerization of chemically synthesised ibuprofen-CoA thioester limitations: The decisive control is the failure: homogenates could not invert free R-ibuprofen even with all cofactors, which locates the species difference in the activation step rather than in the epimerase. exposure: Synthetic R- and S-ibuprofen-CoA thioesters applied to tissue homogenates, with and without cofactors evidence_span: {"source_cache": "artifacts/ibuprofen-research/1859831.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "39dd843ee06ac569e1f2a3af9af6af1639e06694a0f8dcd280065c686bd9902f", "start_char": 0, "end_char": 2138, "text_sha256": "39dd843ee06ac569e1f2a3af9af6af1639e06694a0f8dcd280065c686bd9902f"} [ibu-p1859831] Metabolic stereoisomeric inversion of ibuprofen in mammals. (1991). https://pubmed.ncbi.nlm.nih.gov/1859831/ DOI: 10.1016/0167-4838(91)90164-u

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/

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/ibuprofen-research/4005104.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "81a2d4fb66dca9706eb1bd4119a918b24385de69633f4c4d01692e7c5bd805d1", "start_char": 0, "end_char": 945, "text_sha256": "81a2d4fb66dca9706eb1bd4119a918b24385de69633f4c4d01692e7c5bd805d1"}

experimental_model

Four healthy male subjects given racemic ibuprofen and each enantiomer separately

exposure

800 milligrams racemic ibuprofen and 400 milligrams of each enantiomer, on separate occasions

limitations

The design that matters: giving each enantiomer alone as well as the racemate is the only way to see the inversion and the interaction between them. Four subjects.

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

plain_language

Roughly two thirds of the R half turns into the S half, and none of it comes back.

primary_references

[ibu-p4005104] Stereoselective disposition of ibuprofen enantiomers in man. (1985). https://pubmed.ncbi.nlm.nih.gov/4005104/ DOI: 10.1111/j.1365-2125.1985.tb02694.x

tissue_or_cell_type

Whole body

trigger_kind

biomarker_context Imported condition classification; unverified.

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 71–82

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Four healthy male subjects given racemic ibuprofen and each enantiomer separately · source_derived_draft · unverified_draft

### ibu-sixty-three-percent-inverts A mean of 63 plus or minus 6% of an administered dose of R(-)-ibuprofen was stereospecifically inverted to the S(+) enantiomer in four healthy male subjects, with no measurable inversion of S(+) to R(-), while the kinetics of the individual enantiomers were altered by concurrent administration of the respective optical antipode, likely reflecting an interaction at plasma protein binding sites, and formation of ester glucuronide conjugates stereoselectively favoured the S enantiomer. Condition category: biomarker_context 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: Roughly two thirds of the R half turns into the S half, and none of it comes back. organism: Human tissue_or_cell_type: Whole body experimental_model: Four healthy male subjects given racemic ibuprofen and each enantiomer separately limitations: The design that matters: giving each enantiomer alone as well as the racemate is the only way to see the inversion and the interaction between them. Four subjects. exposure: 800 milligrams racemic ibuprofen and 400 milligrams of each enantiomer, on separate occasions evidence_span: {"source_cache": "artifacts/ibuprofen-research/4005104.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "81a2d4fb66dca9706eb1bd4119a918b24385de69633f4c4d01692e7c5bd805d1", "start_char": 0, "end_char": 945, "text_sha256": "81a2d4fb66dca9706eb1bd4119a918b24385de69633f4c4d01692e7c5bd805d1"} [ibu-p4005104] Stereoselective disposition of ibuprofen enantiomers in man. (1985). https://pubmed.ncbi.nlm.nih.gov/4005104/ DOI: 10.1111/j.1365-2125.1985.tb02694.x

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"}

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