Ketoprofen

Limits on what this shows

• Null findings: Authors of the cardiomyocyte study describe ketoprofen stress as tolerable [23]. Class-level uncoupling data (Horie 1998 [27]) do not name ketoprofen and are not used here.

Regulatory status

No mitochondrial statement in the label text retrieved [1][2].

Tier B, ketoprofen tested

Sci Rep 2020 [23] (human cardiomyocytes, 100 and 200 micromol/L, 24 to 72 hours): slight decrease in the JC-1 ratio, no substantial reduction by TMRE analysis (unlike diclofenac), unchanged viability, preserved proteasome configuration, no ATP measurement. Kasuya et al., J Enzyme Inhib Med Chem 2012 [25] (mouse liver and brain mitochondria, 11 NSAIDs including ketoprofen, abstract via OpenAlex): diflunisal gave the strongest inhibition of octanoic and palmitic acid activation, aspirin also inhibited octanoic acid activation, and diflunisal and mefenamic acid strongly inhibited palmitoyl-CoA formation in brain; ketoprofen was not among the drugs the abstract names as inhibitors, and its effect size was not retrieved. Chirality 1996 [26] (rat liver subcellular fractions, abstract via OpenAlex): (R)-ketoprofen was partly converted to its coenzyme A thioester and inverted to the (S)-enantiomer, primarily in the mitochondrial fraction; hybrid triacylglycerol incorporation was seen in hepatocytes and adipose tissue but not in liver after oral dosing.

Metadata or title only

van Leeuwen et al., Toxicol In Vitro 2012 [24]: eight NSAIDs including ketoprofen were compared for mitochondrial dysfunction, cytochrome P450 activity and active transport; the abstract could not be retrieved from OpenAlex, Crossref or PubMed (reCAPTCHA), so no result is used. A ketoprofen phototoxicity paper (Toxicology 2013, PMID 24128752) reports mitochondrial depolarization after UV exposure from its title only; that is a photosensitivity mechanism, not a nutrient finding, and is not graded.

Mechanism

Named: mild effect on mitochondrial membrane potential and ROS in cardiomyocytes [23]; stereoselective CoA thioester formation in the mitochondrial fraction [26]; competition at acyl-CoA synthetases was tested in mouse mitochondria without a ketoprofen effect named [25]. The ketoprofen-CoA conjugate also inhibits G6PD (see Oxidative stress) [22].

Hard Rule 2 check

Liver enzyme changes or any hepatotoxicity are outcomes and are not mitochondrial findings; none is graded here.

Counter-evidence held on record

Counter-evidence and confounding Cultured human cardiomyocytes at concentrations above expected free plasma levels given more than 99% protein binding; mouse and rat subcellular systems; no in vivo or human mitochondrial endpoint. Framing caution Mechanistic context entry. It does not support a CoQ10, carnitine or other mitochondrial supplement for ketoprofen; no dose is implied.

Limits on what this shows

• Null and in vivo findings: Glowacka et al., Antioxid Redox Signal 2021 [30] (Tier B, rats, ketoprofen 10 mg/kg/day intragastrically for 7 days): "Neither compound affected DNA oxidation in mucosa" (ketoprofen and its hydrogen sulfide-releasing derivative ATB-352), while ketoprofen reduced mucosal hydrogen sulfide content and caused GI damage. Two further ketoprofen oxidative-stress papers were seen as metadata only (abstracts unavailable) and are not used: Alarcon-de-la-Lastra 2000, rat intestinal toxicity of ketoprofen-trometamol and its enantiomers with oxidative stress in the title [33], and Mennillo 2018, rat H4IIE hepatic cells exposed to ketoprofen and dexketoprofen [34]. A Costa 2008 singlet-oxygen paper [29] was checked and excluded because ketoprofen was not confirmed among the drugs named.

Regulatory status

No oxidative-stress or antioxidant statement in the label text retrieved [1][2].

Population evidence (human)

None. No human biomarker study (malondialdehyde, glutathione, superoxide dismutase, F2-isoprostanes) with ketoprofen was retrieved.

Tier B, pro-oxidant direction

Asensio et al., Biochem Pharmacol 2007 [22] (in vitro, ketoprofen coenzyme A conjugate, abstract via a PubMed listing summary): molecular docking and yeast enzyme studies showed the ketoprofen-CoA thioester binds covalently to a cysteine at an allosteric site of glucose-6-phosphate dehydrogenase, and it "was shown to induce the production of reactive oxygen species in Caco-2 cells, where its inhibition of G6PD activity was observed". The thioester itself, not the parent drug, was the active species. Immortalized human cardiomyocyte study, Sci Rep 2020 [23] (Tier B, ketoprofen and diclofenac at 100 and 200 micromol/L for 24 to 72 hours, read from the journal page via a summarizing fetch): dose-dependent rise in reactive oxygen species with ketoprofen, significantly less than diclofenac at 200 micromol/L, no toxicity at any time or concentration, authors' conclusion "tolerable stress events" for ketoprofen versus cell death with diclofenac.

Tier B, reverse (scavenging) direction

Costa, Moutinho, Lima and Fernandes, Biol Pharm Bull 2006 [28] (in vitro, seven arylpropionic acids including ketoprofen, abstract via a summarizing fetch, two passes): ketoprofen showed the highest superoxide scavenging activity and was at or near the top in inhibition of neutrophil-derived reactive oxygen species; the two passes disagreed on the hydrogen peroxide result, so that result is not used. This is a chemistry and cell-free or neutrophil finding. Perontsis et al. 2016 [20] report that copper(II)-ketoprofen complexes had enhanced free radical scavenging compared with free ketoprofen (PubMed condensed abstract), which implies free ketoprofen scavenges less than its copper complex and is not a physiological finding.

Mechanism

Named in vitro: ketoprofen-CoA inhibition of G6PD, which supplies NADPH for glutathione recycling, and ROS induction in Caco-2 cells [22]; mild ROS rise in cardiomyocytes [23]. G6PD inhibition was shown with yeast enzyme and Caco-2 cells, not in human tissue exposed at therapeutic concentrations.

Hard Rule 2 check

Redox status is a context category and not a nutrient deficiency. Direction is unestablished: pro-oxidant potential in two in vitro systems, scavenging in chemical assays, and no DNA oxidation change in the one in vivo rat measure.

Counter-evidence held on record

Counter-evidence and confounding In vitro concentrations (100 to 200 micromol/L) were not matched to free plasma levels, and ketoprofen is more than 99% protein bound [1]; the in vivo rat marker was negative; cell-free scavenging does not predict tissue redox status. Framing caution Not a reason to take antioxidant supplements and not an indication that ketoprofen lowers antioxidant capacity in people. No dose is implied.

Limits on what this shows

• Null and limiting findings: The Moore review states there is no direct evidence linking anemia with low-level blood loss into the bowel [8]. The ketoprofen arm sits below ibuprofen, naproxen and piroxicam on the same table (1.42 versus 1.89 to 2.03 mL/day), which shows drug-to-drug spread and is not evidence of absence of risk. Controlled blood loss data cover about a week in mainly healthy young men, not months of treatment in older patients.
• At-risk subgroups: Older adults, prior ulcer or GI bleeding, concurrent aspirin (label: aspirin lowers ketoprofen protein binding, raises clearance, and the combination is not generally recommended) or warfarin (synergistic GI bleeding) [1][2]; alcohol (Drugs.com food-interaction page, Tier D) [37]; high-dose or multiple topical patches in an older adult [10].

Regulatory status

Ketoprofen capsules label (revised 03/2026) [1] and extended-release label (revised 7/2024) [2], both read through summarizing fetches: "Anemia is sometimes seen in patients receiving NSAIDs, including Ketoprofen Capsules, USP"; patients with signs or symptoms of anemia should have hemoglobin or hematocrit checked; patients on long-term NSAID treatment should have a CBC and chemistry profile checked periodically because serious GI ulceration and bleeding can occur without warning symptoms. Peptic ulcer or GI bleeding occurred "in less than 1% of 1,076 patients" in controlled trials and at a rate greater than 2% in open-label continuation studies in 1,292 patients. The label lists anemia and hemolysis among hemic reactions at under 1% incidence. Label text searched for the words iron and folic: absent [1]. The label states ketoprofen decreases platelet adhesion and aggregation and can prolong bleeding time by about 3 to 4 minutes (summarizer wording) [1].

Population evidence

Moore, Derry and McQuay 2008 [8] (Tier A, systematic review of randomized placebo-controlled trials using autologous chromium-51 labelled erythrocytes, at least 7 days of dosing; ketoprofen in the cohort): Table 2 row "Ketoprofen | 3 | 28 | 1.42" (study arms, participants, weighted mean fecal blood loss mL/day), against placebo 0.76 mL/day (172 participants), baseline 0.46 mL/day, ibuprofen 2.03, naproxen 1.98, piroxicam 1.89 and meloxicam 0.85 on the same table. The review pooled 47 trials and 1,162 participants, predominantly healthy young men with 12% older arthritis patients (OpenAlex abstract); about 5% of NSAID takers lost 5 mL/day or more and 1% lost 10 mL/day or more (pooled for all NSAIDs, not ketoprofen alone). Ketoprofen dose, duration and the original trial citations were not retrieved. Ranlov, Nielsen and Baerenholdt 1983 [9] (Tier A for fecal blood loss, 41 healthy male volunteers, one week of acetylsalicylic acid, ketoprofen, ketoprofen sustained-release capsules and ketoprofen tablets, radiochromium assay): normal fecal blood loss 0.10 to 0.90 mL/day; acetylsalicylic acid produced greater bleeding than equipotent ketoprofen; the sustained-release capsule gave 0.8 mL/day and an IBP tablet formulation significantly more bleeding (abstract via OpenAlex; the immediate-release ketoprofen figure was not in the abstract, and whether this trial is one of the three Moore arms could not be determined). Hirose et al. 2017 [10] (Tier B, case report, topical route): a 74-year-old woman using eight 20 mg ketoprofen patches daily for a long period had fecal occult blood, anemia and small-intestinal ulcers attributed to the patch, which resolved after stopping; iron indices were not in the abstract. Brewer et al., J Rheumatol 1982 [39] (Tier A for tolerability, four-week open-label dose-finding study of ketoprofen in children with juvenile rheumatoid arthritis, 100 rising to 200 mg/m2/day, maximum 320 mg/day; abstract via OpenAlex): laboratory findings showed decreased hemoglobin and hematocrit alongside higher erythrocyte sedimentation rate and blood urea nitrogen, one patient was withdrawn for hematuria, and 20 patients had 39 adverse effects of which six were attributed to ketoprofen; the abstract gives no group size, no values and no iron indices. This is bleeding and hematologic evidence, not an iron measurement.

Mechanism

Label statement: ketoprofen inhibits prostaglandin and leukotriene synthesis in anti-inflammatory models [1]; platelet effects as above. Mucosal injury with occult bleeding is the class-level route; the label names no iron mechanism. No ketoprofen study of ferritin, iron absorption or iron turnover was retrieved.

Hard Rule 2 and 6 checks

GI bleeding and anemia are clinical outcomes, not iron deficiency; deficiency needs measured iron indices. Confounding by indication is presumed (rheumatic disease, aspirin or anticoagulant co-use, age). Direction is loss through bleeding, a toxicity route, not an absorption defect. The Lafrance hyperkalemia cohort and other sibling-dossier sources were not carried over; every source in this entry was opened in this run and tested for ketoprofen (Moore: ketoprofen listed; Ranlov: ketoprofen named in the title).

Counter-evidence held on record

Counter-evidence and confounding Average controlled loss in the ketoprofen arm is a few mL/day from 28 participants in three arms; no cohort compared ferritin before and after starting ketoprofen; the topical case is one patient with documented overuse of eight patches a day. Framing caution This is a toxicity pathway (blood loss), not a dietary or absorption deficiency. New iron deficiency, dark stools or anemia on ketoprofen, including heavy topical patch use, calls for evaluating the bleeding source and the prescription, not an iron supplement by default. No iron dose is recommended here.

Limits on what this shows

• Null findings: No ceruloplasmin, serum copper or copper absorption study of ketoprofen alone was found. A 1976 paper on the role of copper in preventing GI damage by acidic anti-inflammatory drugs (PMID 12259) was seen as a PubMed title only and was not opened (its OpenAlex lookup returned HTTP 429).

Regulatory status

No copper statement in the label text retrieved [1][2].

Population evidence

Twayej, Al-Hakeim, Al-Dujaili and Maes, World J Biol Psychiatry 2020 [19] (clinical study; abstract reconstructed from OpenAlex and read again on a PubMed listing): the aim was the effect of sertraline treatment with and without ketoprofen on serum zinc and copper with immune markers in drug-naive major depression, 133 patients and 40 controls, BDI-II at baseline and 8 weeks. Reported results: lower zinc and copper in depression, sertraline raised zinc and lowered copper, and zinc rose with clinical improvement. No sentence in the abstract text read gives a ketoprofen-arm result, ketoprofen dose or group size, and the full text was not opened, so no ketoprofen effect on copper can be stated. Perontsis et al., J Inorg Biochem 2016 [20] (Tier B, synthetic chemistry; PubMed listing via a summarizing fetch): copper(II)-ketoprofen complexes, with and without nitrogen-donor ligands, were isolated and crystal-structure characterized, bound serum albumins, and interacted with DNA. This shows chemical ability to bind copper, not an effect on body copper.

Mechanism

Named: carboxylate coordination to Cu(II) in vitro [20]. No physiological mechanism for altered copper handling by ketoprofen.

Hard Rule 4 and 6 checks

Any copper effect on ketoprofen's mucosal toxicity would run nutrient to drug and would be a timing or protection question, not a depletion. Depression and rheumatic disease independently alter serum copper (confounding by indication).

Counter-evidence held on record

Counter-evidence and confounding The only measured human data are in depressed patients treated with sertraline, where the disease and the antidepressant both move copper; the ketoprofen contribution is not separable from the abstract. Framing caution No copper supplement is implied. Entry is graded separately from Iron and Zinc.

Limits on what this shows

• Null findings: The lactobacilli growth effect required concentrations above therapeutic plasma levels [32]. No human fecal 16S or metagenomic study of ketoprofen was found. A PubMed listing for ketoprofen and microbiota returned seven records, two relevant here (the rat microbiome paper and the lactobacilli paper) and five on wastewater, plant or enzyme topics; the mouse beta-glucuronidase paper was found as a lead in a sibling dossier's source list and was opened in this run.

Regulatory status

No microbiome statement in the label text retrieved. The label states ketoprofen is conjugated to an unstable acyl-glucuronide that can deconjugate back to the parent drug [1], and that about 80% of a dose is excreted in the urine mainly as the glucuronide [1][2], which is the substrate for the bacterial enzyme in the mouse work below (inference linking label and paper).

Population evidence (animal and in vitro)

Glowacka et al., Antioxid Redox Signal 2021 [30] (Tier B, rats, abstract via OpenAlex): ketoprofen 10 mg/kg/day intragastrically for 7 days "reduced mucosal H2S content inducing GI damage with significantly increased injury score, altered intestinal microbiome profile, and modulation of more than 50% of 36 investigated molecular sensors"; aspirin co-treatment enhanced ketoprofen toxicity and omeprazole 20 mg/kg/day reduced the injury; the abstract does not give which taxa changed. Saitta et al., Xenobiotica 2013 [31] (Tier B, mice, abstract via OpenAlex): a small-molecule inhibitor of bacterial beta-glucuronidase protected against enteropathy from indomethacin, ketoprofen or diclofenac; the proposed mode of action is blocking bacterial cleavage of NSAID glucuronides in the gut lumen. Kruszewska, Zawistowska-Rojek and Tyski, Pol J Microbiol 2023 [32] (Tier B, in vitro): diclofenac, ibuprofen, ketoprofen, dexketoprofen, flurbiprofen and acetylsalicylic acid inhibited growth of lactobacilli at 0.05 to 3.2 mg/mL, concentrations the authors state are well above therapeutic plasma concentrations.

Mechanism

Named: depletion of mucosal hydrogen sulfide with an altered microbiome profile in rats [30]; bacterial beta-glucuronidase cleavage of NSAID conjugates [31]. The microbiome is both a target and a mediator of injury in these models.

Hard Rule 2 check

Mucosal injury and enteropathy are outcomes, not microbiome findings; the entry rests on the one rat profile change [30], which reports altered composition without taxa in the abstract.

Counter-evidence held on record

Counter-evidence and confounding One rat study with a drug dose in mg/kg, mouse work whose subject was an inhibitor rather than ketoprofen, and an in vitro screen at supratherapeutic concentrations; no human cohort and no stratification for acid suppressants or age. Framing caution Mechanistic and context entry. It does not support a probiotic, fiber or antibiotic decision; persistent diarrhea or black stools on ketoprofen belong with the prescriber.

Limits on what this shows

• Null findings: No hemolysis in 34 G6PD-deficient children on short-term ketoprofen lysine [14]. The sickle-cell trial found no efficacy but no tolerability concern in its abstract [13]. No arterial oxygenation or red-cell oxygen affinity measurement with ketoprofen in people was found; the only hemoglobin series is the uncontrolled juvenile arthritis study [39].

Regulatory status

Label [1][2]: anemia warning and hemoglobin or hematocrit check as in the Iron entry; hemic reactions under 1% include hypocoagulability, agranulocytosis, anemia, hemolysis, purpura and thrombocytopenia (summarizer wording); the words aplastic and methemoglobin did not appear in the capsule label text searched [1].

Population evidence

Corda and Carnelli, Pediatria Medica e Chirurgica 1997 [14] (Tier B, uncontrolled case series, abstract via OpenAlex): 19 girls with intermediate erythrocyte G6PD deficiency, 14 hemizygous boys and one fully deficient girl (34 children, 4 months to 16 years) received ketoprofen lysine salt rectally, 30 or 60 mg two or three times daily (about 2.5 mg/kg), for respiratory tract disease; fever resolved within two days in 80% and "no systemic or local adverse events or hemolysis" appeared clinically or in laboratory tests, over short duration. Bartolucci et al., Blood 2009 [13] (Tier A for tolerability and efficacy, phase 3 double-blind placebo-controlled trial, 66 sickle-cell vaso-occlusive episodes, ketoprofen 300 mg daily for five days): no difference in crisis duration or secondary endpoints; the abstract reports no hemoglobin or hemolysis outcome. Brewer 1982 [39] (children with juvenile rheumatoid arthritis, four weeks of ketoprofen, open label): hemoglobin and hematocrit fell, but the same abstract reports a rise in erythrocyte sedimentation rate, no control arm and no iron or oxygen delivery measure, so the fall cannot be separated from disease activity, hemodilution or blood loss. None of these studies measured oxygen delivery or utilization.

Mechanism

Three routes in the label and general pharmacology, none shown to lower oxygen delivery at therapeutic dosing: blood loss anemia (Iron entry), fluid retention with dilution (label edema wording), and rare hematologic reactions listed under 1% [1]. A mechanistic signal exists in the oxidative-stress literature: ketoprofen coenzyme A thioester irreversibly inhibited glucose-6-phosphate dehydrogenase in a yeast enzyme assay and induced reactive oxygen species in Caco-2 cells [22]. That work did not use red cells, so any link to erythrocyte oxidant handling is an inference and is not a finding. A separate light-dependent mechanism exists: He et al., Photochem Photobiol 2003 [40] (Tier B, purified red blood cells in vitro, abstract via OpenAlex) found that UVA plus ketoprofen formed methemoglobin-derived radicals, dependent on UVA dose and ketoprofen concentration, while ketoprofen alone or UVA alone produced minimal radical formation. That is a photosensitization reaction (the label lists photosensitivity at under 1% [1]), requires UVA exposure, was not measured in people and is not graded as a systemic oxygen-delivery effect.

Hard Rule 2 check

Anemia is an outcome, not a nutrient deficiency, and a rare drug reaction is an adverse event, not an oxygen-delivery deficiency. Ketoprofen has no intended hemodynamic oxygen-demand effect to clarify. This entry is a context and monitoring flag only; the label basis is Tier A for the existence of the warning, not for any measured oxygen-delivery change, so the entry stays yellow.

Counter-evidence held on record

Counter-evidence and confounding Postmarketing and label under-1% events have no denominator; the G6PD series is small, uncontrolled and short; the sickle-cell trial was an efficacy trial in adults with a different question. Framing caution Do not read this as an oxygen-carrying deficiency that supplements can fix. Unexplained fatigue, pallor, jaundice or dark urine on ketoprofen is a prescriber question; no iron, folate or antioxidant supplement is implied.

Limits on what this shows

• Null findings: No ketoprofen ATP null was found either. The cardiomyocyte viability result was unchanged at 100 and 200 micromol/L [23].

Regulatory status

No ATP or energy-metabolism statement in the label text retrieved [1][2].

CLASS EXTRAPOLATION

Horie et al., J Pharmacol Exp Ther 1998 [27] (Tier C for ketoprofen): 18 acidic NSAIDs (3 salicylic acids, 3 anthranilic acids, 6 arylacetic acids, 6 arylpropionic acids) in freshly isolated rat hepatocytes; the abstract (paraphrased by a summarizing fetch, which could not reproduce it verbatim) attributes hepatotoxicity to an NSAID-induced fall in ATP, probably through uncoupling of oxidative phosphorylation, and non-cytotoxic NSAIDs did not lower ATP. Cohort test: only eight drugs are named in the text read (diflunisal, flufenamic acid, mefenamic acid, tolfenamic acid, diclofenac, indomethacin, acemetacin, flurbiprofen) and ketoprofen is not among them; it may sit among the six arylpropionic acids, but that is not confirmed, so ketoprofen is treated as NOT in the cohort. Capped at yellow.

Ketoprofen-specific data

None for ATP. The cardiomyocyte paper [23] stated that no ATP measurement was made; Kasuya 2012 [25] tested acyl-CoA synthetase activity, a fatty acid activation step, not ATP output.

Mechanism

Class-level uncoupling named for cytotoxic acidic NSAIDs [27]; unknown for ketoprofen, whose mitochondrial membrane potential effect was slight [23].

Hard Rule 7 note

Entered separately from Mitochondrial burden and Oxygen delivery/utilization; it shares background sources with Mitochondrial burden (see Overlap map).

Counter-evidence held on record

Counter-evidence and confounding Hepatocyte ATP loss was linked to cytotoxic doses in vitro; nothing links it to ATP shortage in patients on ketoprofen, and ketoprofen was not confirmed in the cohort. Framing caution Not an indication of low energy in people taking ketoprofen and not a reason for any supplement. No dose is implied.