{"id":"f6d815da-4b34-5a31-beba-885169f29645","stable_key":"f8641d02-8413-5bd8-92e9-62ad49286e81:asa-antagonism-not-seen-in-vivo","predicate":"preserves_measured_pool","statement":"Several authors have reported that salicylate blocks and reverses aspirin inhibition of prostaglandin synthesis by platelets and arterial wall, but when rats were given sodium salicylate at 15 or 100 milligrams per kilogram two minutes before aspirin at 10 milligrams per kilogram, a significant antithrombotic effect of aspirin was observed in all cases regardless of prior salicylate administration with results similar to aspirin alone, so competition between salicylate and aspirin as reported in vitro does not appear to significantly affect the in vivo antithrombotic action in this model.","claim_class":"observational","status":"source_derived_draft","evidence_grade":"ungraded","direction":"neutral","is_public":true,"mechanism_event_id":"0d2b5f81-ada9-53fd-8653-467579f90175","mechanism_event_label":"The metabolite gets in the drug’s way in a test tube, but giving it first did not stop aspirin working in a rat.","subject":{"id":"5739797a-3699-591b-95fd-f8b80e612713","slug":"salicylate","display_name":"Salicylate / salicylic acid","entity_type_key":"small_molecule"},"object":{"id":"4b772fbf-8a5b-57cd-ad5d-f41634a4688c","slug":"arterial-thrombosis","display_name":"Arterial thrombosis","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"0d2b5f81-ada9-53fd-8653-467579f90175","stable_key":"f8641d02-8413-5bd8-92e9-62ad49286e81:asa-antagonism-not-seen-in-vivo-event","event_type":"observed_intervention","label":"The metabolite gets in the drug’s way in a test tube, but giving it first did not stop aspirin working in a rat.","description":"Several authors have reported that salicylate blocks and reverses aspirin inhibition of prostaglandin synthesis by platelets and arterial wall, but when rats were given sodium salicylate at 15 or 100 milligrams per kilogram two minutes before aspirin at 10 milligrams per kilogram, a significant antithrombotic effect of aspirin was observed in all cases regardless of prior salicylate administration with results similar to aspirin alone, so competition between salicylate and aspirin as reported in vitro does not appear to significantly affect the in vivo antithrombotic action in this model.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"8ac405bf-3ea0-539a-8e5e-abf503dc7081","slug":"aspirin","display_name":"Aspirin / acetylsalicylic acid","entity_type_key":"drug"},"role":"protected_drug","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"5739797a-3699-591b-95fd-f8b80e612713","slug":"salicylate","display_name":"Salicylate / salicylic acid","entity_type_key":"small_molecule"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"4b772fbf-8a5b-57cd-ad5d-f41634a4688c","slug":"arterial-thrombosis","display_name":"Arterial thrombosis","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/aspirin-research/6792646.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"55b09486e54c42e6ecdac3476a0ae8b9d9819f06b5b01a9fc33087fd621a9c82\", \"start_char\": 0, \"end_char\": 767, \"text_sha256\": \"55b09486e54c42e6ecdac3476a0ae8b9d9819f06b5b01a9fc33087fd621a9c82\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Electrically induced carotid artery thrombosis in male rats with salicylate pretreatment","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Sodium salicylate 15 or 100 milligrams per kilogram intravenously two minutes before aspirin 10 milligrams per kilogram","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"A direct in vivo test of an in vitro observation. One model, one species, and thrombus generation measured indirectly by downstream temperature.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes.","comparator":null,"unit":null,"notes":"","entity":{"slug":"aspirin","display_name":"Aspirin / acetylsalicylic acid","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Rat","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"The metabolite gets in the drug’s way in a test tube, but giving it first did not stop aspirin working in a rat.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[asa-p6792646] Non-interference by salicylate with aspirin inhibition of arterial thrombosis in rats. (1981). https://pubmed.ncbi.nlm.nih.gov/6792646/ DOI: 10.1016/0161-4630(81)90052-5","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Carotid artery","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"f34a7604-66ad-5a45-ad24-466a38936a2b","evidence_kind":"source_excerpt","locator":"Lines 520-531","start_line":520,"end_line":531,"excerpt":"### asa-antagonism-not-seen-in-vivo\nSeveral authors have reported that salicylate blocks and reverses aspirin inhibition of prostaglandin synthesis by platelets and arterial wall, but when rats were given sodium salicylate at 15 or 100 milligrams per kilogram two minutes before aspirin at 10 milligrams per kilogram, a significant antithrombotic effect of aspirin was observed in all cases regardless of prior salicylate administration with results similar to aspirin alone, so competition between salicylate and aspirin as reported in vitro does not appear to significantly affect the in vivo antithrombotic action in this model.\nCondition category: normal\nnutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes.\nplain_language: The metabolite gets in the drug’s way in a test tube, but giving it first did not stop aspirin working in a rat.\norganism: Rat\ntissue_or_cell_type: Carotid artery\nexperimental_model: Electrically induced carotid artery thrombosis in male rats with salicylate pretreatment\nlimitations: A direct in vivo test of an in vitro observation. One model, one species, and thrombus generation measured indirectly by downstream temperature.\nexposure: Sodium salicylate 15 or 100 milligrams per kilogram intravenously two minutes before aspirin 10 milligrams per kilogram\nevidence_span: {\"source_cache\": \"artifacts/aspirin-research/6792646.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"55b09486e54c42e6ecdac3476a0ae8b9d9819f06b5b01a9fc33087fd621a9c82\", \"start_char\": 0, \"end_char\": 767, \"text_sha256\": \"55b09486e54c42e6ecdac3476a0ae8b9d9819f06b5b01a9fc33087fd621a9c82\"}\n[asa-p6792646] Non-interference by salicylate with aspirin inhibition of arterial thrombosis in rats. (1981). https://pubmed.ncbi.nlm.nih.gov/6792646/ DOI: 10.1016/0161-4630(81)90052-5","model_system":"Electrically induced carotid artery thrombosis in male rats with salicylate pretreatment","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [asa-p6792646] Non-interference by salicylate with aspirin inhibition of arterial thrombosis in rats. (1981). https://pubmed.ncbi.nlm.nih.gov/6792646/ DOI: 10.1016/0161-4630(81)90052-5","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"712cf519-cd27-5a8b-9e2f-961a98d7a27e","stable_key":"import-f8641d02-8413-5bd8-92e9-62ad49286e81","title":"Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (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":"93dd4343051c131e40d4fc3c95a978cd65478c13dcdb3f2d42507c49b09cb647","revision_id":"694e8ee7-49ca-5e6c-b58b-8ba8f82c2ad8","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"e1c2f316-8e95-5188-8cbe-53558b4be53b","title":"Does the metabolite get in the way of the parent drug?","kind":"qualification","status":"open","why":"Crystallography places salicylic acid in the cyclooxygenase channel at a site consistent with an antagonistic effect on aspirin, a later and higher-resolution structure finds its binding pose reflects the enzyme-inhibitor complex immediately before acetylation, and the 1981 report notes that several authors had found salicylate blocks and reverses aspirin inhibition of prostaglandin synthesis in vitro. Against that, giving rats salicylate at up to ten times the aspirin dose two minutes beforehand did not reduce aspirin’s antithrombotic effect at all. The structural and in vitro evidence that the two compete for one site is strong; whether the competition matters depends on the concentrations each reaches at the enzyme and on timing, and the in vivo test is a single rat thrombosis model with intravenous dosing. The mechanism is recorded as real and its clinical consequence as unestablished.","resolution":"Unresolved; needs review.","created_at":"2026-09-22 06:15:08","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/e1c2f316-8e95-5188-8cbe-53558b4be53b","sides":[{"conflict_id":"e1c2f316-8e95-5188-8cbe-53558b4be53b","ordinal":0,"label":"The breakdown product sits in the same place the drug needs to reach, and gets in its way.","revision_id":"694e8ee7-49ca-5e6c-b58b-8ba8f82c2ad8","start_line":143,"end_line":154,"quote":"### asa-salicylate-antagonises-at-the-site\nIn the crystal structure of the inactivated enzyme the product salicylic acid was observed binding at a site consistent with its antagonistic effect on aspirin activity.\nCondition category: normal\nnutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes.\nplain_language: The breakdown product sits in the same place the drug needs to reach, and gets in its way.\norganism: Enzyme\ntissue_or_cell_type: Crystallised prostaglandin H2 synthase-1\nexperimental_model: X-ray crystal structure at 3.4 angstrom of prostaglandin H2 synthase-1 inactivated by a potent aspirin analogue\nlimitations: Direct structural evidence rather than inference from mutants, though at modest resolution and using an analogue rather than aspirin itself.\nexposure: 2-bromoacetoxy-benzoic acid acetylation, with salicylic acid soaked into the structure\nevidence_span: {\"source_cache\": \"artifacts/aspirin-research/7552725.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"dd61431f20eb312313942bc8a89f970d5d2e33600b32abe692f20d9d5c57d7b1\", \"start_char\": 0, \"end_char\": 751, \"text_sha256\": \"dd61431f20eb312313942bc8a89f970d5d2e33600b32abe692f20d9d5c57d7b1\"}\n[asa-p7552725] The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. (1995). https://pubmed.ncbi.nlm.nih.gov/7552725/ DOI: 10.1038/nsb0895-637","source_key":"import-f8641d02-8413-5bd8-92e9-62ad49286e81","source_title":"Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22)","claim_ids":["e1968986-5ee8-5b67-9d91-0baa0d0c1236"]},{"conflict_id":"e1c2f316-8e95-5188-8cbe-53558b4be53b","ordinal":1,"label":"The metabolite gets in the drug’s way in a test tube, but giving it first did not stop aspirin working in a rat.","revision_id":"694e8ee7-49ca-5e6c-b58b-8ba8f82c2ad8","start_line":520,"end_line":531,"quote":"### asa-antagonism-not-seen-in-vivo\nSeveral authors have reported that salicylate blocks and reverses aspirin inhibition of prostaglandin synthesis by platelets and arterial wall, but when rats were given sodium salicylate at 15 or 100 milligrams per kilogram two minutes before aspirin at 10 milligrams per kilogram, a significant antithrombotic effect of aspirin was observed in all cases regardless of prior salicylate administration with results similar to aspirin alone, so competition between salicylate and aspirin as reported in vitro does not appear to significantly affect the in vivo antithrombotic action in this model.\nCondition category: normal\nnutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes.\nplain_language: The metabolite gets in the drug’s way in a test tube, but giving it first did not stop aspirin working in a rat.\norganism: Rat\ntissue_or_cell_type: Carotid artery\nexperimental_model: Electrically induced carotid artery thrombosis in male rats with salicylate pretreatment\nlimitations: A direct in vivo test of an in vitro observation. One model, one species, and thrombus generation measured indirectly by downstream temperature.\nexposure: Sodium salicylate 15 or 100 milligrams per kilogram intravenously two minutes before aspirin 10 milligrams per kilogram\nevidence_span: {\"source_cache\": \"artifacts/aspirin-research/6792646.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"55b09486e54c42e6ecdac3476a0ae8b9d9819f06b5b01a9fc33087fd621a9c82\", \"start_char\": 0, \"end_char\": 767, \"text_sha256\": \"55b09486e54c42e6ecdac3476a0ae8b9d9819f06b5b01a9fc33087fd621a9c82\"}\n[asa-p6792646] Non-interference by salicylate with aspirin inhibition of arterial thrombosis in rats. (1981). https://pubmed.ncbi.nlm.nih.gov/6792646/ DOI: 10.1016/0161-4630(81)90052-5","source_key":"import-f8641d02-8413-5bd8-92e9-62ad49286e81","source_title":"Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22)","claim_ids":["f6d815da-4b34-5a31-beba-885169f29645"]}]}],"corrections":[],"research":null}