Fenoprofen

Limits on what this shows

• Null and limiting findings: No fenoprofen respirometry, membrane potential, lactate or muscle biopsy data in animals or humans were retrieved. The Europe PMC query for fenoprofen with mitochondria in title or abstract returned one hit (Knadler [23]; query listing [33]); PubMed queries returned empty stub pages (inconclusive). Mahmud reports good-GI-tolerability drugs did not uncouple [25]. In vitro concentrations in these systems are not compared to human free plasma levels (fenoprofen is 99% albumin bound [1][2]).

Regulatory status

The label text read does not discuss mitochondrial effects [1][2].

Population evidence

Tier B, fenoprofen in the cohort: Knadler and Hall 1990, Chirality [23] (rat tissue homogenates and subcellular fractions, abstract read via Europe PMC): only the R-enantiomers of fenoprofen and ibuprofen formed arylpropionyl-CoA thioesters (the abstract gives "(R)-fenoprofen (64%)" and "(R)-ibuprofen (33%)" without a stated denominator in the summarizer text); flurbiprofen enantiomers and the S-forms did not; in liver, thioester formation occurred in mitochondria and microsomes but not cytosol; liver was at least 50-fold more efficient than other tissues. No respiration, membrane potential or fatty-acid oxidation endpoint was reported. Tier C (CLASS EXTRAPOLATION): Mahmud et al. 1996, Arthritis Rheum [25] (isolated rat liver mitochondria, abstract via an index record and summarizing fetch): conventional NSAIDs and acidic prodrugs stimulated respiration at 0.02 to 2.7 micromolar and became inhibitory at higher concentrations, uncoupling potency inversely correlated with pKa; fenoprofen is not named; modified flurbiprofen compounds and nabumetone did not uncouple. Horie et al. 1998, J Pharmacol Exp Ther [24] (18 acidic NSAIDs in rat hepatocytes, abstract only): the eight named cytotoxic drugs were diflunisal, flufenamic, mefenamic and tolfenamic acids, diclofenac, indomethacin, acemetacin and flurbiprofen; six arylpropionic acids were tested but only flurbiprofen was named, so whether fenoprofen was among them could not be established. CLASS EXTRAPOLATION cohort test: fenoprofen NOT shown to be in the Mahmud or Horie cohorts.

Mechanism

Proposed, not demonstrated for fenoprofen: acyl-CoA thioester formation in mitochondria [23] (a pathway whose consequence for mitochondrial CoA or fatty-acid oxidation was not tested in the source) and, for acidic NSAIDs as a group, uncoupling of oxidative phosphorylation [24][25].

Hard Rule 2 and 6 checks

Mitochondrial effects in vitro are the drug acting on a structure, not a nutrient deficiency; no cofactor (CoQ10, carnitine, B vitamins) was measured. Class extrapolation labeled and capped at yellow.

Counter-evidence held on record

Counter-evidence and confounding Thioester formation is a metabolic step for chiral inversion of 2-arylpropionic acids, not evidence of toxicity; hepatotoxicity of NSAIDs is rare relative to exposure (label lists hepatic reactions under 1% [1]). Framing caution Not a reason to take CoQ10, carnitine or any antioxidant. A laboratory signal and a mechanistic possibility only; no measured energy deficit in patients.

Limits on what this shows

• Null and limiting findings: No pro-oxidant or antioxidant-depleting finding was retrieved. The Cu(II) and Zn(II) fenoprofen complexes that showed hydrogen peroxide reduction and radical scavenging [28][30] are synthetic compounds, not the parent drug, and are not counted.

Regulatory status

Not addressed in the label text read [1][2].

Population evidence

Tier B, fenoprofen in the cohort. (a) Costa, Moutinho, Lima and Fernandes, Biol Pharm Bull 2006 [21] (abstract on J-STAGE, read via summarizing fetch): seven arylpropionic acid NSAIDs were screened in non-cellular systems and in human neutrophil oxidative burst; fenoprofen appears in the rank orders for hydroxyl radical and for peroxynitrite scavenging and is absent from the superoxide, hydrogen peroxide, nitric oxide, myeloperoxidase and neutrophil ROS orders; its position and magnitude could not be read reliably from the summarized abstract. (b) Rahimi-Tesiye, Rajabi-Maham, Azizi and Hosseini, Pharmacol Res Perspect 2025 [22] (abstract via an OpenAlex record): male Wistar rats, five groups, fenoprofen 10, 20 and 40 mg/kg given before each pentylenetetrazole injection; serum malondialdehyde, superoxide dismutase and glutathione peroxidase and hippocampal Nrf2 and HO-1 were measured; the abstract reports "antioxidant effects" and reversal of the PTZ-induced fall in Nrf2/HO-1 expression, but the direction for each serum marker, the group size and the route were not stated in the text read.

Mechanism

Direct chemical scavenging [21] and activation of the Nrf2/HO-1 pathway in a seizure model [22]. No glutathione, MDA or antioxidant enzyme measurement in fenoprofen users was retrieved.

Hard Rule 2 check

A drug's test-tube scavenging or animal-model marker shift is not a nutrient entry and does not imply any antioxidant vitamin need or benefit.

Counter-evidence held on record

Counter-evidence and confounding In vitro screens use concentrations that may not be reached in vivo; NSAID mitochondrial effects (see Mitochondrial burden) point the other way and were not measured for fenoprofen. The rat study used a disease model, not healthy animals. Framing caution Not evidence that fenoprofen is antioxidant in patients, and not evidence of antioxidant depletion. No antioxidant supplement is implied.

Limits on what this shows

• Null and limiting findings: No ferritin, hemoglobin or iron balance outcome with fenoprofen was retrieved (PubMed queries for fenoprofen with iron or hemoglobin returned empty stub pages, which are inconclusive, and the Europe PMC anemia query was refused HTTP 429; see Sources access note). Exposures were 7 to 14 days. Fenoprofen bleeding was consistently lower than full-dose aspirin (2.2 vs 5.0 and 2.46 vs 4.96 mL/day). Moore states most of the pooled participants were healthy young men and only 12% older people with arthritis (abstract, OpenAlex rendering) [11].
• At-risk subgroups: Older adults, prior ulcer or GI bleeding, anticoagulant co-use (label: fenoprofen and warfarin have a synergistic effect on bleeding), analgesic-dose aspirin co-use (label: not generally recommended), and SSRIs or SNRIs, which the label lists as adding bleeding risk [1][2].

Regulatory status

Label (summarizing fetch of DailyMed, 12/2025 revision) [1]: serious GI bleeding, ulceration and perforation are warnings; in the adverse reaction section GI events were the most common reaction (20.8% on fenoprofen versus 16.9% on placebo), with gastritis, peptic ulcer and GI hemorrhage each under 1%. Anemia: "Anemia has occurred in NSAID-treated patients," with hemoglobin or hematocrit monitoring if symptoms appear [1][2]. Approximately 1% of NSAID-treated patients over 3 to 6 months developed upper GI ulcers, gross bleeding or perforation (class statement, Drugs.com rendering) [2]. The label text read mentions iron only as a colorant [1][2].

Population evidence

Tier A, fenoprofen in every cohort below. (a) Moore, Derry and McQuay 2008 [11], systematic review of 47 randomized chromium-51 trials (1,162 participants): Table 2 as read through a summarizing fetch of the PDF lists fenoprofen as 4 study arms, 62 participants, weighted mean 1.86 mL/day, against placebo arms 0.76 mL/day (14 arms, 172 participants), baseline 0.46 mL/day (950 participants) and aspirin above 1,800 mg/day 5.01 mL/day (29 arms, 361 participants); fenoprofen is not in Table 3 (proportion above 5 mL/day), and no confidence interval for it was seen. (b) Loebl et al. 1977, JAMA [7]: 14 patients with rheumatoid arthritis, randomized to aspirin 4 g/day or fenoprofen calcium 2.4 g/day for 7 days each after acetaminophen periods; fecal blood loss 5.0 mL/day aspirin, 2.2 mL/day fenoprofen, 0.8 mL/day acetaminophen; gastroscopy found antral ulceration or mucosal lesions in 7 on aspirin, 1 on fenoprofen and 0 on acetaminophen. (c) Chernish et al. 1979, Arthritis Rheum [8]: 16 men, double-blind crossover, fenoprofen 2,400 mg/day for one week: 2.46 mL fenoprofen, 4.96 mL aspirin (3,904 mg/day), 0.79 mL placebo (aspirin higher than the others, P below 0.05). (d) Ryan et al. 1987, Clin Pharmacol Ther [9]: 32 healthy men, parallel, fenoprofen 600 mg four times daily for 2 weeks: mean daily fecal blood loss 1.686 +/- 0.858 mL (plain) versus 1.104 +/- 0.961 mL (enteric-coated), P = 0.03; endoscopy at one center showed mucosal damage without symptoms and 4 of 16 subjects had asymptomatic duodenal ulcers. (e) Ridolfo et al. 1973 [10]: fenoprofen and aspirin both produced measurable microbleeding in normal men, fenoprofen less (abstract only; numbers garbled in the record).

Independence and overlap

Loebl and Chernish are crossover trials of the type Moore pooled, so they are probably among its 4 fenoprofen arms (not verified, because the Table 2 read did not list arms). Ryan 1987 is a parallel-group design and is probably outside the Moore set. Treat (a) to (c) as one pooled body and (d) as a separate measurement; both show a measurable rise in fecal blood loss with fenoprofen.

Mechanism

Named at the level of mucosal injury: endoscopic lesions in 1 of 14 (Loebl [7]), mucosal damage in the Ryan volunteers [9], and the label warnings on GI ulceration and bleeding [1]. No mechanism for the bleeding beyond the class GI warning is stated in the label text read.

Hard Rule 2 and 6 checks

GI bleeding and anemia are clinical outcomes and anemia is not iron deficiency; what is graded here is the measured blood loss, which is a loss pathway for iron-containing blood, not a measured iron deficit. Confounding by indication is reduced because the largest datasets are randomized or crossover with placebo or acetaminophen arms; in rheumatoid arthritis patients, disease and aspirin history remain confounders (Loebl, n = 14). No class extrapolation is used in this entry. Customer-string boundary required by the orange rule: "short-term fecal blood loss measured at anti-inflammatory doses; iron status not measured."

Counter-evidence held on record

Counter-evidence and confounding A rise of roughly 1 mL/day over placebo is modest; whether it translates into iron deficiency depends on duration, baseline iron stores, diet and co-medication, none of which these studies tested. Aspirin comparator arms bled more. Most subjects were healthy volunteers. Framing caution This is a blood loss pathway caused by the drug, not a dietary or absorption deficiency. New fatigue, black stools or a low hemoglobin on fenoprofen 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

• Why no grade: Dual condition met. (1) No Tier B or C evidence for a copper status effect. The four PubMed records returned for fenoprofen with copper [28] are synthetic coordination chemistry: copper(II) complexes of fenoprofen with ibuprofen, loxoprofen and clonixin characterized in vitro and in silico (Malis 2021; Geromichalou 2022); Cu2(fen)4 complexes dosed to mice for 28 days in the diet, where all exposed groups showed raised plasma urea and no copper or ceruloplasmin value is reported (Gumilar 2012); and a mononuclear copper(II) fenoprofen complex versus fenoprofen calcium in female mice, with writhing inhibition 78.9% versus 46.2% and ulcer index about 22 versus 79 mm2 (Agotegaray 2014). In every record copper is the carrier in a new compound given to the animal; none measures the effect of fenoprofen on copper status, absorption, excretion or ceruloplasmin, so none is nutrient evidence and none supports even yellow. (2) No circulating claim: Lima Memorial names iron and sodium for NSAIDs generally [31], People's Pharmacy covers folate [32], and the consumer label text has no mineral statement [5]; none mentions copper for fenoprofen.

Channels tried

Label text for copper, iron, zinc and minerals (none found beyond iron oxide colorants) [1][2]. PubMed listing "fenoprofen copper" (4 records, all synthetic complexes, listed above) [28]. PubMed listing "fenoprofen glomerular filtration" (3 records; one is the Gumilar complex study) [29]. Consumer and circulating pages [5][31][32]. Blocked or exhausted: WebSearch (shared budget used up before copper queries ran), an Europe PMC query combining fenoprofen with zinc, copper, ceruloplasmin and trace element (HTTP 429, not retried), PubMed "fenoprofen ceruloplasmin" not attempted after repeated throttling.

Genuine gap or tooling-limited

Probably a genuine gap for copper status with fenoprofen: the PubMed term search that completed returned only complex chemistry. Partly tooling-limited because ceruloplasmin and rheumatoid serum copper queries were not completed and no full texts were opened. Re-check with working PubMed access (fenoprofen with ceruloplasmin, serum copper, rheumatoid arthritis trace elements) before treating the gap as closed.

Limits on what this shows

• Null and limiting findings: No significant alpha diversity change for NSAIDs [27]. Fenoprofen-specific queries (PubMed fenoprofen microbiota, Europe PMC fenoprofen microbiota and microbiome) were refused HTTP 429, so a fenoprofen-in-cohort microbiome study was not excluded; this is tooling-limited.

Regulatory status

Not addressed in the label text read [1][2].

Population evidence

Tier C for fenoprofen. Le Bastard et al., Aliment Pharmacol Ther 2018 [27] (systematic review, PRISMA, culture-independent methods; abstract reconstructed from an OpenAlex record): NSAIDs and metformin showed no significant alpha diversity change; beta diversity was significantly altered by all drugs studied except NSAIDs; NSAIDs were associated with increases in Gammaproteobacteria (including Enterobacter, Escherichia, Klebsiella, Citrobacter) or Enterococcaceae. CLASS EXTRAPOLATION cohort test: fenoprofen NOT named in the abstract, so it is not shown to be in the cohort.

Mechanism

Proposed class-level mucosal injury and altered bile acid or drug metabolism; not examined for fenoprofen in any source opened.

Hard Rule 6 check

Class extrapolation, capped at yellow, fenoprofen not shown in the cohort.

Counter-evidence held on record

Counter-evidence and confounding Age, disease, PPI co-use and diet are strong confounders in human NSAID microbiome studies, and a pooled NSAID class cannot attribute change to fenoprofen. Framing caution A theoretical class signal only. No probiotic or prebiotic recommendation is implied.

Limits on what this shows

• Null findings: No fenoprofen arterial oxygenation, red-cell oxygen affinity or methemoglobin report was retrieved; PubMed queries for "fenoprofen hemolytic anemia" returned the single Shirey record in the one listing that loaded (a broader query returned off-topic records), and the "fenoprofen hemoglobin" and "fenoprofen iron" queries returned empty stub pages (inconclusive).

Regulatory status

Label [1][2] (summarizing fetches): anemia statement as in the Iron entry; hematologic reactions under 1% include hemolytic anemia, aplastic anemia, agranulocytosis and pancytopenia. Consumer text (Drugs.com) lists "low red blood cells (anemia)" with pale skin, unusual tiredness and light-headedness as warning signs [5].

Population evidence

Tier B. Shirey et al. 1988, Am J Clin Pathol [19] (PubMed listing summary, abstract only): a 70-year-old man developed "severe immune intravascular hemolysis and renal failure" after fenoprofen; red cells were sensitized with IgG and C3d; the serum reacted with normal red cells with or without drug and albumin inhibited that reactivity, which the authors explained by HPLC measurement of fenoprofen in neat serum and by albumin binding the drug. A French case report of acute thrombocytopenic purpura (platelets 24,000 per mm3) on fenoprofen (Barrier 1979, seen as a PubMed listing summary) [20] concerns platelets, not red cells, and is context only. Hemoglobin series with fenoprofen: none retrieved (the blood loss data are in the Iron entry).

Mechanism

Drug-dependent antibody-mediated hemolysis (case report) and blood loss; neither is an oxygen-delivery deficiency mechanism in a nutrient sense.

Hard Rule 2 check

Anemia and hemolysis are adverse events and outcomes, not oxygen-delivery deficiencies, and fenoprofen has no intended hemodynamic oxygen-demand effect to clarify. The label basis is Tier A for the existence of the warning only; the single case report is Tier B. Entry kept separate from Iron and from ATP production per Hard Rule 7.

Counter-evidence held on record

Counter-evidence and confounding A single case report has no denominator; label frequencies (under 1%) are rare. Blood loss anemia is covered under Iron. Framing caution Not an oxygen-carrying deficiency that supplements can fix. Dark urine, jaundice, pallor or unexplained fatigue on fenoprofen is a prescriber question; no iron, folate or antioxidant supplement is implied.

Limits on what this shows

• Null and limiting findings: No ATP, phosphocreatine or fatigue endpoint in fenoprofen-treated animals or humans was retrieved. Concentration relative to plasma was not established.

Regulatory status

Not addressed in the label text read [1][2].

Population evidence

Tier C for fenoprofen. Horie et al. 1998 [24] (abstract only): "All of the cytotoxic NSAIDs and diphenylamine extensively decreased hepatocellular ATP content," attributed by the authors to uncoupling of mitochondrial oxidative phosphorylation; the word fenoprofen does not appear in the abstract. Mahmud 1996 [25] supplies the uncoupling concept in isolated mitochondria without naming fenoprofen. CLASS EXTRAPOLATION cohort test: fenoprofen NOT shown to be in either cohort. Fenoprofen shares the 2-arylpropionic acid scaffold with flurbiprofen, which was named, so the idea is plausible but is not fenoprofen evidence.

Mechanism

Probable uncoupling of oxidative phosphorylation (authors' inference) [24]; not shown for fenoprofen.

Hard Rule 2, 6 and 7 checks

Reduced ATP in injured cells is drug toxicity, not a nutrient deficiency; "low energy" is not graded as a symptom entry. Kept separate from Mitochondrial burden and Oxygen delivery per Hard Rule 7 but not independent evidence (see Overlap map). Class extrapolation capped at yellow.

Counter-evidence held on record

Counter-evidence and confounding Group-level finding from a single hepatocyte study without a fenoprofen-specific value. Fatigue in treated patients is confounded by the underlying disease. Framing caution Not evidence of an energy deficit that supplements can fix. No ATP, CoQ10 or carnitine recommendation is implied.