{"id":"3fa0097c-5e27-5817-a3b8-31115a6b5037","stable_key":"3238e4f0-8d45-5c72-8624-6e9a8b20527c:ibu-no-selectivity-in-whole-blood","predicate":"limits","statement":"Measurement of the inhibitory potency of non-steroidal anti-inflammatory drugs on cyclooxygenase isoforms is strongly influenced by variations in experimental conditions, the concentration of protein in the assay medium being particularly important because these drugs are highly protein bound in vivo so that assays based on human whole blood provide the most suitable test system, and of the drugs investigated only meloxicam showed selectivity for cyclooxygenase-2 at therapeutically relevant concentrations while standard drugs such as naproxen inhibited both isoforms to an equal degree.","claim_class":"observational","status":"source_derived_draft","evidence_grade":"ungraded","direction":"neutral","is_public":true,"mechanism_event_id":"2fa64711-5698-5681-aa3f-205772847fea","mechanism_event_label":"Measured in blood rather than in a tube of enzyme, the ordinary anti-inflammatories hit both enzymes about equally.","subject":{"id":"34983199-a31e-5364-9caf-b530d5ee2c99","slug":"whole-blood-assay","display_name":"The human whole blood assay of cyclooxygenase activity","entity_type_key":"cellular_process"},"object":{"id":"52a2d1bd-f96d-5a87-84de-682aa1db8672","slug":"cox-selectivity-ratio","display_name":"The ratio of cyclooxygenase-1 to cyclooxygenase-2 inhibitory potency","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"2fa64711-5698-5681-aa3f-205772847fea","stable_key":"3238e4f0-8d45-5c72-8624-6e9a8b20527c:ibu-no-selectivity-in-whole-blood-event","event_type":"observed_intervention","label":"Measured in blood rather than in a tube of enzyme, the ordinary anti-inflammatories hit both enzymes about equally.","description":"Measurement of the inhibitory potency of non-steroidal anti-inflammatory drugs on cyclooxygenase isoforms is strongly influenced by variations in experimental conditions, the concentration of protein in the assay medium being particularly important because these drugs are highly protein bound in vivo so that assays based on human whole blood provide the most suitable test system, and of the drugs investigated only meloxicam showed selectivity for cyclooxygenase-2 at therapeutically relevant concentrations while standard drugs such as naproxen inhibited both isoforms to an equal degree.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"a504fc54-daff-5717-b53b-979a66d0bf96","slug":"meloxicam","display_name":"Meloxicam","entity_type_key":"drug"},"role":"selective_comparator","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"105efa29-5f66-5005-bea2-8082ae7bd180","slug":"naproxen","display_name":"Naproxen","entity_type_key":"drug"},"role":"nonselective_comparator","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"90ebf099-f2e7-59ec-8477-1c6c2c6cda83","slug":"plasma-protein-binding-ibu","display_name":"Unbound fraction of drug in plasma","entity_type_key":"cellular_process"},"role":"confounding_property","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"34983199-a31e-5364-9caf-b530d5ee2c99","slug":"whole-blood-assay","display_name":"The human whole blood assay of cyclooxygenase activity","entity_type_key":"cellular_process"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"52a2d1bd-f96d-5a87-84de-682aa1db8672","slug":"cox-selectivity-ratio","display_name":"The ratio of cyclooxygenase-1 to cyclooxygenase-2 inhibitory potency","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/ibuprofen-research/9219317.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"d3edafe44ec9bf9e15505ffebb96add5467f8874fe8b585ce3878c473f250714\", \"start_char\": 0, \"end_char\": 1162, \"text_sha256\": \"d3edafe44ec9bf9e15505ffebb96add5467f8874fe8b585ce3878c473f250714\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Comparison of cyclooxygenase inhibitory potency across assay systems, using the human whole blood assay","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Standard non-steroidal anti-inflammatory drugs compared at therapeutically relevant concentrations","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Argues that the whole blood assay is the appropriate test because these drugs are highly protein bound. It reports conclusions about the class, with naproxen named rather than ibuprofen.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"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.","comparator":null,"unit":null,"notes":"","entity":{"slug":"ibuprofen","display_name":"Ibuprofen","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Human","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Measured in blood rather than in a tube of enzyme, the ordinary anti-inflammatories hit both enzymes about equally.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[ibu-p9219317] Differentiating among nonsteroidal antiinflammatory drugs by pharmacokinetic and pharmacodynamic profiles. (1997). https://pubmed.ncbi.nlm.nih.gov/9219317/ DOI: 10.1016/s0049-0172(97)80050-9","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Whole blood","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"1bcc54aa-161c-5e4c-8ba1-9230c8e33689","evidence_kind":"source_excerpt","locator":"Lines 344-355","start_line":344,"end_line":355,"excerpt":"### ibu-no-selectivity-in-whole-blood\nMeasurement of the inhibitory potency of non-steroidal anti-inflammatory drugs on cyclooxygenase isoforms is strongly influenced by variations in experimental conditions, the concentration of protein in the assay medium being particularly important because these drugs are highly protein bound in vivo so that assays based on human whole blood provide the most suitable test system, and of the drugs investigated only meloxicam showed selectivity for cyclooxygenase-2 at therapeutically relevant concentrations while standard drugs such as naproxen inhibited both isoforms to an equal degree.\nCondition category: normal\nnutrient_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.\nplain_language: Measured in blood rather than in a tube of enzyme, the ordinary anti-inflammatories hit both enzymes about equally.\norganism: Human\ntissue_or_cell_type: Whole blood\nexperimental_model: Comparison of cyclooxygenase inhibitory potency across assay systems, using the human whole blood assay\nlimitations: Argues that the whole blood assay is the appropriate test because these drugs are highly protein bound. It reports conclusions about the class, with naproxen named rather than ibuprofen.\nexposure: Standard non-steroidal anti-inflammatory drugs compared at therapeutically relevant concentrations\nevidence_span: {\"source_cache\": \"artifacts/ibuprofen-research/9219317.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"d3edafe44ec9bf9e15505ffebb96add5467f8874fe8b585ce3878c473f250714\", \"start_char\": 0, \"end_char\": 1162, \"text_sha256\": \"d3edafe44ec9bf9e15505ffebb96add5467f8874fe8b585ce3878c473f250714\"}\n[ibu-p9219317] Differentiating among nonsteroidal antiinflammatory drugs by pharmacokinetic and pharmacodynamic profiles. (1997). https://pubmed.ncbi.nlm.nih.gov/9219317/ DOI: 10.1016/s0049-0172(97)80050-9","model_system":"Comparison of cyclooxygenase inhibitory potency across assay systems, using the human whole blood assay","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [ibu-p9219317] Differentiating among nonsteroidal antiinflammatory drugs by pharmacokinetic and pharmacodynamic profiles. (1997). https://pubmed.ncbi.nlm.nih.gov/9219317/ DOI: 10.1016/s0049-0172(97)80050-9","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"31c4939d-f520-55c0-973b-224743caf245","stable_key":"import-3238e4f0-8d45-5c72-8624-6e9a8b20527c","title":"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)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"cc2b388178f97f5906b66ecbe441fc5c86d51fd645947c5260fb0b4bdb4bcd21","revision_id":"0b4e5c65-05d3-5430-a4cd-8d6a03647dcb","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"7cda81d8-db31-5349-a0b3-038f1d698623","title":"Is ibuprofen selective between the two cyclooxygenases?","kind":"context_difference","status":"open","why":"Measured on purified and recombinant enzyme, S-ibuprofen was 27-fold more potent against cyclooxygenase-1 than against cyclooxygenase-2, which would make the drug appreciably cyclooxygenase-1 selective, and the two enantiomers differed 32-fold at cyclooxygenase-1 while showing no selectivity at all at cyclooxygenase-2. Measured in human whole blood at therapeutically relevant concentrations, standard drugs of this class inhibited both isoforms to an equal degree and only meloxicam showed selectivity. A third record shows why the two need not agree: potencies and selectivities determined in intact cells depend on substrate concentration and differ from those obtained in cell-free microsomal or purified preparations, and protein binding, which is high and stereoselective for this drug, is absent from purified systems. The ratio is therefore a property of the assay as much as of the drug, and no single selectivity figure for ibuprofen is supported here.","resolution":"Unresolved; needs review.","created_at":"2026-09-22 14:28:23","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/7cda81d8-db31-5349-a0b3-038f1d698623","sides":[{"conflict_id":"7cda81d8-db31-5349-a0b3-038f1d698623","ordinal":0,"label":"At the first enzyme one hand is thirty to ninety times stronger; at the second enzyme the two hands are indistinguishable.","revision_id":"0b4e5c65-05d3-5430-a4cd-8d6a03647dcb","start_line":318,"end_line":329,"quote":"### ibu-thirty-two-fold-at-cox1\nThe S(+) isomer of ibuprofen was 32-, 41- and 96-fold more potent than the R(-) isomer for inhibition of prostaglandin endoperoxide H synthase-1 activity, human platelet aggregation and serotonin secretion respectively, while on prostaglandin endoperoxide H synthase-2 the ibuprofen isomers showed no selectivity, and indomethacin, S(+)-ibuprofen and S(+)-naproxen were 6-, 27- and 5-fold more potent as inhibitors of synthase-1 than of synthase-2.\nCondition category: normal\nnutrient_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.\nplain_language: At the first enzyme one hand is thirty to ninety times stronger; at the second enzyme the two hands are indistinguishable.\norganism: Rat, human and sheep systems\ntissue_or_cell_type: Transfected cells, hepatoma cells, platelets and purified enzyme\nexperimental_model: Reporter and enzyme assays comparing ibuprofen isomers against naproxen and indomethacin across four readouts\nlimitations: The only record here that measures both enantiomers on the same panel, which is what makes the fold-differences meaningful. Several different assay systems are combined.\nexposure: S(+)- and R(-)-ibuprofen compared directly on cyclooxygenase-1 and -2, platelet function and nuclear receptor activation\nevidence_span: {\"source_cache\": \"artifacts/ibuprofen-research/11755111.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"1dd77f4a1eebd7777285c424b1731f4744d0fa593e62cfbde0a92dbb6242b239\", \"start_char\": 0, \"end_char\": 2074, \"text_sha256\": \"1dd77f4a1eebd7777285c424b1731f4744d0fa593e62cfbde0a92dbb6242b239\"}\n[ibu-p11755111] Activation of peroxisome proliferator-activated receptor isoforms and inhibition of prostaglandin H(2) synthases by ibuprofen, naproxen, and indomethacin. (2001). https://pubmed.ncbi.nlm.nih.gov/11755111/ DOI: 10.1016/s0006-2952(01)00822-x","source_key":"import-3238e4f0-8d45-5c72-8624-6e9a8b20527c","source_title":"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)","claim_ids":["a7c4dd5c-b0e4-5366-8bd3-e6283469bc27"]},{"conflict_id":"7cda81d8-db31-5349-a0b3-038f1d698623","ordinal":1,"label":"Measured in blood rather than in a tube of enzyme, the ordinary anti-inflammatories hit both enzymes about equally.","revision_id":"0b4e5c65-05d3-5430-a4cd-8d6a03647dcb","start_line":344,"end_line":355,"quote":"### ibu-no-selectivity-in-whole-blood\nMeasurement of the inhibitory potency of non-steroidal anti-inflammatory drugs on cyclooxygenase isoforms is strongly influenced by variations in experimental conditions, the concentration of protein in the assay medium being particularly important because these drugs are highly protein bound in vivo so that assays based on human whole blood provide the most suitable test system, and of the drugs investigated only meloxicam showed selectivity for cyclooxygenase-2 at therapeutically relevant concentrations while standard drugs such as naproxen inhibited both isoforms to an equal degree.\nCondition category: normal\nnutrient_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.\nplain_language: Measured in blood rather than in a tube of enzyme, the ordinary anti-inflammatories hit both enzymes about equally.\norganism: Human\ntissue_or_cell_type: Whole blood\nexperimental_model: Comparison of cyclooxygenase inhibitory potency across assay systems, using the human whole blood assay\nlimitations: Argues that the whole blood assay is the appropriate test because these drugs are highly protein bound. It reports conclusions about the class, with naproxen named rather than ibuprofen.\nexposure: Standard non-steroidal anti-inflammatory drugs compared at therapeutically relevant concentrations\nevidence_span: {\"source_cache\": \"artifacts/ibuprofen-research/9219317.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"d3edafe44ec9bf9e15505ffebb96add5467f8874fe8b585ce3878c473f250714\", \"start_char\": 0, \"end_char\": 1162, \"text_sha256\": \"d3edafe44ec9bf9e15505ffebb96add5467f8874fe8b585ce3878c473f250714\"}\n[ibu-p9219317] Differentiating among nonsteroidal antiinflammatory drugs by pharmacokinetic and pharmacodynamic profiles. (1997). https://pubmed.ncbi.nlm.nih.gov/9219317/ DOI: 10.1016/s0049-0172(97)80050-9","source_key":"import-3238e4f0-8d45-5c72-8624-6e9a8b20527c","source_title":"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)","claim_ids":["3fa0097c-5e27-5817-a3b8-31115a6b5037"]}]}],"corrections":[],"research":null}