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MyDeficiencies

Entacapone

COMT inhibitor, nitrocatechol, peripherally restricted

Also sold as Comtan.

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Findings for this medication

Research about this medication, graded for how strongly each finding can be attributed to it. Nothing here describes your own levels.

Entacapone has little of the classical depletion machinery this dossier series is built to catch. Its own structured FDA labeling, retrieved directly, describes a drug that undergoes essentially no CYP450-mediated oxidative metabolism (isomerization to the cis-isomer followed by direct glucuronidation instead), inhibits CYP enzymes only at concentrations far above clinical exposure, and is eliminated mainly unchanged or as its glucuronide through bile and feces (about 90%) rather than through the kidney (about 10%), so it has no renal-tubular-wasting mechanism to speak of. The one clearly documented, drug-confirmed classical mechanism is absorption interference through iron chelation: the label itself states entacapone "is a chelator of iron" and describes "a tendency towards decreasing serum iron concentrations" in its own controlled trials, but also states plainly that those same trials found no difference in anemia rates or hemoglobin levels after one year of treatment. Two recent, methodologically serious ex vivo studies, including one in Nature Microbiology, extend this same chelation chemistry to the gut: entacapone measurably depletes microbiota-accessible iron in human fecal communities, reshapes which bacteria thrive (favoring iron-scavenging, antimicrobial-resistance-carrying taxa), and is itself bioaccumulated by 80-96% of tested gut bacteria through what looks like a siderophore-transporter-dependent route. That is graded here as a genuinely new, still-underappreciated yellow finding, not folded into the bounded orange Iron entry it mechanistically shares.

COMT inhibitor, nitrocatechol, peripherally restricted · ATC N04BX02 · also sold as Comtan; Stalevo (fixed-dose combination with carbidopa/levodopa) · reviewed 2026-10-01. This describes research about the medication. It does not say anything about your own levels or health.

How to read the evidence grades

These colours describe how strongly a finding can be attributed to the medication in the research. They are not a severity score and they say nothing about your own health.

Grades describe how strongly a finding can be attributed to Entacapone in the research — not how common it is, how serious it would be, and not anything about you personally.

Red — Severe
Two or more independent Tier A sources, this drug in the cohort, the nutrient directly measured, consistent direction, clinically meaningful magnitude, a named mechanism, no substantial contradicting Tier A evidence.
Orange — Moderate
At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit.
Yellow — Low
Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction.
Not graded — disclosed evidence gap
Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result.Source definition: Not gradeable under the rules above because nothing has been measured. Published as a documented gap, never as reassurance that there is no effect.

What the research found

Red tier

Red — Severe

See study details

No nutrient or category in this dossier reached red.

Full detail and limits

What the grade means here: Two or more independent Tier A sources, this drug in the cohort, the nutrient directly measured, consistent direction, clinically meaningful magnitude, a named mechanism, no substantial contradicting Tier A evidence. Empty

Limits on what this shows

  • What would fill this tier: A second, independently conducted, adequately powered randomized trial directly measuring entacapone's effect (not levodopa's) on a nutrient or functional marker, with a magnitude and direction consistent with an existing Tier A finding and no substantial contradicting Tier A result.

Why empty

Entacapone's elimination (about 90% biliary/fecal, 10% urine, no clinically significant CYP induction) leaves it little classical depletion machinery to begin with. Its one clear, drug-confirmed direct mechanism, iron chelation, is itself bounded by the sponsor's own controlled-trial data showing no difference in anemia incidence or hemoglobin at one year, which rules out "clinically meaningful magnitude" for red. The homocysteine/B-vitamin pathway has real Tier A human data on both sides of the question (some showing entacapone lowers homocysteine versus levodopa alone, the strongest-design study showing it does not), which rules out "consistent direction" for red.

Potassium

Orange — Moderate

See study details

Entacapone's own labeled diarrhea/colitis adverse effect, not a systemic drug action, is the documented route to potassium loss, and it affects roughly 1 in 10 patients.

Full detail and limits

What the grade means here: At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit. Orange, electrolyte loss bounded to drug-induced diarrhea (about 10% of patients)

Limits on what this shows

  • Key negative/null findings: The large majority of patients (roughly 90%) do not develop diarrhea on entacapone; electrolyte loss is a consequence of the adverse event, not a universal drug effect.
  • At-risk subgroups: Patients who develop diarrhea within the first 4-12 weeks of therapy; the 1.7% who discontinued for diarrhea mark the more severe tail of this subgroup [1].

Regulatory status

FDA-approved structured product label: diarrhea in 10% of entacapone-treated patients (60/603) versus 4% on placebo (16/400); the label states "diarrhea may be associated with weight loss, dehydration, and hypokalemia," typically presenting 4-12 weeks after starting but possible at any time, and warns this may reflect drug-induced microscopic colitis [1].

Population evidence

The same pooled trial population cited in the label (603 entacapone-treated vs. 400 placebo patients for the diarrhea comparison); 10 of 603 patients (1.7%) discontinued entacapone specifically for diarrhea [1]. No dedicated entacapone-specific serum-potassium measurement study was located.

Mechanism

GI fluid and electrolyte loss secondary to a labeled adverse effect (diarrhea, possible microscopic colitis), not a direct renal or absorptive potassium mechanism of entacapone itself.

Counter-evidence held on record

No entacapone-specific electrolyte trial was located to either confirm or refute magnitude; this entry rests on the label's own adverse-event and warning language rather than a dedicated electrolyte study. This is a depletion-direction, GI-loss mechanism, not a retention effect, but supplementation is not indicated preemptively in the roughly 90% of patients who never develop diarrhea. If diarrhea develops, hydration and electrolyte status (not routine potassium supplementation) is the monitoring priority, together with evaluation for drug-induced microscopic colitis per the label's warning, with prescriber involvement.

Vitamin B12, folate and B6, homocysteine-methylation pathway

Yellow — Low

See study details

Chronic levodopa therapy reliably raises homocysteine through its own COMT-mediated methylation; whether adding entacapone meaningfully changes that picture is genuinely unsettled across the available randomized and observational data, and the one purpose-built RCT found B12/folate, not entacapone, to be the effective intervention.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, direction contested, mechanistically a levodopa effect

Limits on what this shows

  • Key negative/null findings: The Di Rocco/Werner RCT, the strongest single design in this set, found no significant homocysteine-lowering effect of entacapone itself [11]; a separate 100-patient cross-sectional study reached the same no-effect conclusion [10].
  • At-risk subgroups: Patients with low or low-normal baseline folate appear most likely to show any entacapone-associated change, per the Zesiewicz review [7]. A case-control study examined, but did not establish causation for, a homocysteine-polyneuropathy association in patients on levodopa and entacapone [15]; this is reported here as outcome context, not graded as a deficiency, since polyneuropathy is a clinical outcome rather than a measured nutrient level (Hard Rule 2).

Regulatory status

Not addressed in the FDA label; this entry rests entirely on the published clinical literature.

Mechanism

Named (Step 2, mechanism D: cofactor antagonism). COMT methylates catechol substrates, including levodopa (to 3-O-methyldopa), using S-adenosylmethionine (SAM) as the methyl donor; each methylation generates S-adenosylhomocysteine, which hydrolyzes to homocysteine. This reaction is part of levodopa's own metabolism, not an independent mechanism of entacapone. A review by Zesiewicz et al. (2006) frames peripheral COMT inhibition as mechanistically positioned to blunt this specific reaction, "theoretically prevent or reduce levodopa-induced [hyperhomocysteinemia]," while noting trial results conflict and may depend on baseline folate status [7].

Population evidence, lower-homocysteine direction

A 240-subject cross-sectional study, restricted to the MTHFR 677 CC genotype and stratified into 4 groups of 60 (levodopa+entacapone, levodopa alone, levodopa-naive, healthy control), found homocysteine of approximately 15.1 micromol/L in the levodopa+entacapone group versus 20.4 micromol/L levodopa-alone versus 9.1 micromol/L healthy control, i.e. partial but incomplete mitigation [8]. A separate cross-sectional study is titled "Reduced plasma homocysteine levels in levodopa/entacapone treated Parkinson patients" [9]; this review confirmed the title, authorship, journal, and year via OpenAlex but could not independently retrieve its full quantitative results this session (abstract text unavailable through the channels reached; see Sources access notes).

Population evidence, no-effect direction

A 100-patient, three-arm cross-sectional study (levodopa+dopamine agonist; levodopa+entacapone+dopamine agonist; dopamine agonist alone) found homocysteine elevated above normal laboratory values in both levodopa-containing groups, with the authors concluding entacapone "does not effectively prevent hyperhomocysteinemia" [10]. The only randomized controlled trial located, comparing folate+B12, entacapone, and a control arm in patients with Parkinson's disease, found that folate and B12, not entacapone, reduced levodopa-induced homocysteine elevation, and the authors flagged uncertainty over whether their observation window was long enough to detect a slower-developing entacapone effect [11]. A second RCT specifically examining vitamin B12, folate, and entacapone together was identified (title, journal, year, and PMID confirmed) but its results were not independently retrieved this session [12].

Additional titles identified, not independently verified

Two further entacapone-homocysteine studies were located in the same PubMed search (titles, authors, years, and PMIDs confirmed) but their abstracts were not independently retrieved this session due to repeated access blocks: a 2005 Neurology report [13] and a 2010 Neurological Sciences study [14].

Counter-evidence held on record

Genuine, not suppressed, counter-evidence against an entacapone depletion effect: the Di Rocco RCT and the Kocer cross-sectional study both found no significant entacapone effect on homocysteine beyond levodopa alone [10][11]. Do not present this as "entacapone depletes B12, folate, or B6." The homocysteine elevation belongs mechanistically to levodopa; entacapone's own direction of effect, where measured, trends neutral-to-protective and was never found worse than levodopa alone in any source located this session. No supplementation dose is recommended by this entry (yellow tier); clinicians already monitor homocysteine, B12, and folate in long-term levodopa therapy for reasons independent of entacapone specifically.

The five body-system areas

Each finding is counted once, in a single area. Where a study is mentioned in a second area it is context only.

Mitochondrial Burden

Each finding below is counted once, in this area only.

Mitochondrial burden

Yellow — Low

See study details

Entacapone itself has been tested directly and repeatedly, not merely assumed guilty by class association, and still shows no mitochondrial injury signal at concentrations far above therapeutic plasma levels, unlike its same-class relative tolcapone.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, no effect at clinical exposure; class-mate tolcapone is the toxic outlier

Limits on what this shows

  • Key negative/null findings: All three independently retrieved entacapone-specific studies are null/reassuring for mitochondrial structure, membrane potential, and energy production at the concentrations tested [16][17][18].
  • At-risk subgroups: None identified at therapeutic exposure; the supratherapeutic in vitro ceiling tested (200 micromol/L) is well above reported clinical plasma levels.

Mechanism

Mitochondrial interference (Step 2, mechanism E) is biologically plausible for this drug class because tolcapone, also a COMT inhibitor, carries a boxed hepatotoxicity warning mechanistically linked to mitochondrial uncoupling. The cohort test (Hard Rule 6) matters directly here: entacapone itself, not just its class, has been tested in each source below.

Population evidence

Sprague-Dawley rat in vivo electron-microscopy study: entacapone produced no conformational changes in liver mitochondria or skeletal muscle, using 2,4-dinitrophenol as a positive uncoupling control [16]. A separate isolated-mitochondria/whole-animal study is titled "Entacapone... does not impair mitochondrial energy production" (title, authors, journal, and PMID confirmed; full abstract text not independently retrieved this session) [17]. Human HepaRG hepatocyte-like cells plus isolated mouse liver mitochondria: entacapone caused no cytotoxicity and no ATP depletion up to 200 micromol/L, while tolcapone inhibited respiratory complexes I, II, and IV and depleted ATP with an estimated IC50 of 100 micromol/L; both compounds showed uncoupling in isolated mitochondria, but tolcapone was consistently more potent, and the concentrations at which tolcapone showed toxicity are supratherapeutic relative to typical clinical plasma levels [18]. A related entacapone/tolcapone membrane-potential study [19] and newer comparative cellular-toxicity [20] and fatty-acid-metabolism [21] papers using both drugs were identified in the same PubMed search but not independently opened this session (title/author/journal/PMID confirmed only; see Sources access notes).

Counter-evidence held on record

None found contradicting these null results for entacapone specifically; tolcapone's documented toxicity belongs to a different molecule and is not carried onto entacapone per the cohort test. This is a reassurance/reverse-direction entry, not a deficiency finding, included specifically to prevent a plausible but unsupported class-extrapolation from tolcapone's hepatotoxicity profile onto entacapone. No supplement or monitoring action is implied by this entry.

Oxidative Stress

Each finding below is counted once, in this area only.

Oxidative stress

Yellow — Low

See study details

In vitro, entacapone itself scavenges reactive species more effectively than vitamin C or E on several assays, and adding it to chronic high-dose L-DOPA did not increase oxidative-damage markers in a non-human-primate model.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, entacapone's own antioxidant chemistry, not a depletion signal

Limits on what this shows

  • Key negative/null findings: The primate in vivo data found no oxidative-damage increase from adding entacapone to L-DOPA [23], consistent in direction with the in vitro antioxidant finding [22].
  • At-risk subgroups: None identified.

Mechanism

Reverse-direction finding under the Step 2 addendum: entacapone's own nitrocatechol structure is redox-active.

Population evidence

In vitro human umbilical vein endothelial cell study: entacapone at 10-20 micromol/L scavenged 60-83% of DPPH radicals, showed roughly 8-fold stronger hypochlorous-acid scavenging than vitamin C, 8-30% stronger peroxynitrite scavenging than vitamin C, and protected cells against hydrogen-peroxide-induced death comparably to vitamin E [22]. Chronic high-dose L-DOPA, alone or combined with entacapone, cynomolgus monkey (non-human primate) model: no increase in lipid peroxidation, protein carbonyls, or oxidative DNA damage in the nigrostriatal pathway of normal animals, and no impairment of dopaminergic neuron function, versus untreated animals [23].

Counter-evidence held on record

None located; both identified entacapone-specific sources point the same (protective) direction. Do not read this as grounds for antioxidant supplementation, and do not present entacapone itself as a clinical substitute for vitamin C or E. This is in vitro radical-scavenging chemistry plus one animal model, not a clinical antioxidant-therapy claim.

Copper and Iron Balance

Copper and iron are assessed separately. Nothing here is counted twice.

Iron

Orange — Moderate

See study details

Entacapone binds non-heme iron in the gut; the sponsor's own controlled-trial data show a measured tendency toward lower serum iron with no corresponding rise in anemia incidence or fall in hemoglobin after one year of treatment.

Full detail and limits

What the grade means here: At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit. Orange, GI chelation, bounded by no anemia signal at 1 year

Limits on what this shows

  • Key negative/null findings: No difference in anemia incidence or hemoglobin concentration at one year, in the label's own controlled trials [1]. This is the specific finding that bounds the entry to orange rather than red.
  • At-risk subgroups: Patients co-administering oral iron supplements or iron-fortified products at the same time as entacapone, where the chelation interaction is timing-dependent rather than a permanent absorption block; no pediatric- or renal-impairment-specific iron data were located.

Regulatory status

FDA-approved structured product label: "Entacapone is a chelator of iron," with "a tendency towards decreasing serum iron concentrations" in controlled trials, but "controlled trials showed no differences in anemia rates or hemoglobin levels" after one year of treatment [1].

Population evidence

The FDA-reviewed controlled-trial dataset cited directly in the label is the only population-level evidence located [1]. The chelation chemistry itself was independently characterized in aqueous solution by Orama et al. (1997, J Pharm Sci), confirming entacapone forms stable complexes with Fe(III) at physiologically relevant pH, a drug-specific physicochemical study rather than a clinical trial [4].

Mechanism

Named (Step 2, mechanism A: absorption interference via chelation). The same chelation chemistry extends to the gut-bacterial level: an ex vivo human fecal-community study found entacapone complexes and depletes microbiota-accessible iron, and replenishing iron rescued the microbial growth entacapone had suppressed, directly demonstrating the causal link between the chelation and downstream effects [5] (see Gut microbiome risk entry and Overlap map).

Counter-evidence held on record

The one-year anemia/hemoglobin data from the label is itself the counter-evidence that bounds this entry to "measured but subclinical" rather than a severe finding. This is a genuine, depletion-direction absorption-interference mechanism, not a retention/excess effect, but it does not support an iron-supplementation recommendation. It supports separating any iron-containing product from entacapone dosing and, for patients on long-term combined use, periodic serum iron/ferritin monitoring rather than preemptive supplementation. No dose of iron is recommended by this entry.

Copper

Not graded — disclosed evidence gap

See study details

No grade assigned: no mechanism, no drug-specific or class-level evidence at any tier, and no circulating consumer claim located to rebut.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Why no grade: No present mechanism was identified at Step 2: COMT uses Mg2+, not Cu2+, as its catalytic cofactor; the copper-dependent enzyme in catecholamine metabolism is dopamine-beta-hydroxylase, which entacapone does not inhibit or otherwise target. No Tier B or Tier C drug-specific or class-level evidence was located, and no circulating consumer claim about entacapone and copper was found to rebut as white. The dual condition for ungraded (Step 7) is met.

Channels tried

PubMed search-listing page, combined query "entacapone AND (copper OR ceruloplasmin OR magnesium OR zinc)": 4 results, all irrelevant (an analytical-chemistry quantification method, a general clinical-trials digest, a QSAR structure-activity modeling paper, and a COMT enzyme-kinetics paper establishing Mg-dependence, not copper-relatedness). Crossref API search, "entacapone copper": 10 results, all irrelevant pharmacopeial/regulatory records (USP monographs, EU EPAR filings, a drug-handbook chapter). Circulating-claim check: a mainstream consumer drug-information site (drugs.com) was fetched directly and its entacapone monograph explicitly listed no nutrient, vitamin, or mineral claims of any kind [3]. Europe PMC, Semantic Scholar, and DailyMed's web interface returned network-policy 403 or repeated 429 responses for the entirety of this session and were not usable as additional channels for this category specifically; broader supplement-retailer and "drug-induced nutrient depletion handbook"-style sites were not reachable through the tooling available this session.

Assessment

Most likely a genuine literature gap, consistent with the PK prescreen (no absorption-interference mechanism for copper specifically, unlike the confirmed iron mechanism) and the mechanism screen (no copper-dependent enzyme in entacapone's pharmacology). This should be revisited in a future revision if Europe PMC, Semantic Scholar, or DailyMed access is restored, since those channels were not usable this session.

Gut Microbiome Risk

Each finding below is counted once, in this area only.

Gut microbiome risk

Yellow — Low

See study details

Two independent, recent, drug-specific studies, including one in Nature Microbiology, show entacapone directly depletes microbiota-accessible iron in human fecal communities and reshapes which bacteria thrive, favoring iron-scavenging, antimicrobial-resistance-carrying taxa.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, iron-sequestration-driven disruption, ex vivo, drug-specific

Limits on what this shows

  • Key negative/null findings: None located; both sources point the same direction.
  • At-risk subgroups: None established in living patients; both studies are ex vivo (donor fecal samples/isolated bacterial strains), not in vivo clinical cohorts, which is why this stays yellow rather than advancing to orange or red despite the strength and consistency of the mechanistic data.

Mechanism

Microbiome disruption via metal sequestration (Step 2, mechanism G, extended), mechanistically the same iron-chelating chemistry described in the Iron entry (see Overlap map).

Population evidence

Ex vivo human fecal-community study (quantitative microbiome profiling, long-read metagenomics, stable isotope probing, single-cell chemical imaging), published in Nature Microbiology: entacapone complexed and depleted available iron, producing gut microbiome composition and functional changes; replenishing microbiota-accessible iron rescued the microbial growth entacapone had suppressed; iron starvation selectively favored iron-scavenging taxa carrying antimicrobial-resistance and virulence genes; entacapone's effect on microbial activity was more pronounced than on raw taxonomic abundance, and larger than a comparator psychiatric drug tested in the same study [5]. A second, 2025 ex vivo study using alkyne-tagged entacapone derivatives, fluorescence-activated cell sorting, and 16S rRNA gene sequencing in donor fecal communities and E. coli strains found 80-96% of bacteria across donors bioaccumulated the tagged drug, with evidence that a siderophore transporter is involved in uptake; the tagged drug retained the biological activity of the original, causing significant reductions in microbial loads and compositional shifts across donors [6].

Counter-evidence held on record

None found; this is a genuinely new (2024-2025) research area with no contradicting data yet published, and no in vivo human clinical confirmation yet either. This is ex vivo mechanistic evidence, not a clinical finding of dysbiosis, GI illness, or nutrient malabsorption in living patients on entacapone, and it does not support probiotic or iron self-supplementation. It is flagged here because it is new, well-conducted, and shares its root mechanism with the Iron entry.

Oxygen and ATP Output

Oxygen delivery and ATP production are assessed separately. Nothing here is counted twice.

Oxygen delivery/utilization

Yellow — Low

See study details

The same FDA-reviewed trial data documenting entacapone's iron-chelating tendency explicitly found no difference in anemia incidence or hemoglobin concentration after one year of treatment.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, no measured hemoglobin or anemia signal despite a plausible iron-chelation pathway

Limits on what this shows

  • Key negative/null findings: This entire entry is a negative/reassuring finding, by design.
  • At-risk subgroups: None established.

Mechanism

Theoretically downstream of the Iron entry's chelation mechanism (reduced iron availability could, in principle, impair hemoglobin synthesis), but Hard Rule 2 requires this be tested directly rather than assumed, and the label's own one-year data directly tested it.

Regulatory status

FDA-approved structured product label: "controlled trials showed no differences in anemia rates or hemoglobin levels" after one year of treatment [1].

Population evidence

Same pooled controlled-trial population cited in the label [1]. A targeted PubMed search combining entacapone with oxygen, hematocrit, erythropoietin, and hemoglobin terms returned no dedicated entacapone hematocrit/erythropoietin study.

Counter-evidence held on record

None found contradicting the label's one-year anemia/hemoglobin data. Kept as its own entry rather than merged into Iron, per Hard Rule 7, even though the two share the same underlying trial dataset (see Overlap map). Nothing here implies a need to monitor hemoglobin specifically because of entacapone.

ATP production

Yellow — Low

See study details

The same direct, entacapone-specific testing that found no mitochondrial structural injury also measured ATP content directly and found no depletion, in contrast to tolcapone.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, no depletion at concentrations far above clinical exposure

Limits on what this shows

  • Key negative/null findings: Both identified entacapone-specific sources are null/reassuring for ATP production.
  • At-risk subgroups: None identified at therapeutic exposure.

Mechanism

Same underlying mechanism screen as Mitochondrial burden; kept as an independent entry per Hard Rule 7 because ATP synthesis is conceptually distinct from mitochondrial structure/membrane integrity.

Population evidence

Human HepaRG cells plus isolated mouse liver mitochondria: "entacapone caused no cytotoxicity and no ATP depletion up to 200 micromol/L," while tolcapone's ATP-depletion IC50 was approximately 100 micromol/L [18]. A 1997 study titled "Entacapone... does not impair mitochondrial energy production" was identified and its title, authors, journal, and PMID independently confirmed, though its full abstract text was not retrieved this session [17].

Counter-evidence held on record

None found for entacapone specifically. Reassurance entry, not a deficiency finding; see Mitochondrial burden entry and Overlap map for the shared evidence base.

How the body handles this medication

Metabolism
Isomerization to the cis-isomer followed by direct glucuronidation; no clinically significant CYP450-mediated oxidative metabolism. In vitro, entacapone inhibits several CYP enzymes, but "only at very high concentrations," not reached at clinical doses.FDA-approved structured product label, entacapone, Clinical Pharmacology / Drug Interactions (via openFDA)
Absorption
Rapid, Tmax approximately 1 hour; absolute oral bioavailability about 35%; pharmacokinetics linear across a 5-800 mg range; food does not affect entacapone's pharmacokinetics.FDA-approved structured product label, entacapone, Clinical Pharmacology (via openFDA)
Elimination
About 90% of labeled parent drug and metabolite is excreted in feces (chiefly biliary excretion), about 10% in urine; not a drug with a clinically significant renal-tubular-wasting mechanism.FDA-approved structured product label, entacapone, Clinical Pharmacology (via openFDA)
Mineral-chelating interaction
Entacapone is a chelator of iron; the label describes a measured tendency toward decreasing serum iron concentrations in controlled trials, with no difference in anemia rates or hemoglobin levels after one year. Independently, entacapone's iron(III)-chelating behavior has been characterized directly in aqueous solution.FDA-approved structured product label, entacapone (via openFDA); Orama et al. 1997, J Pharm Sci
Hepatic impairment
AUC and Cmax approximately double in patients with documented liver disease; the label advises caution in hepatic impairment.FDA-approved structured product label, entacapone, Precautions (via openFDA)
GI adverse-effect profile
Diarrhea occurred in 10% of entacapone-treated patients (603 total) versus 4% on placebo (400 total) in pooled trials, typically presenting 4-12 weeks after starting; the label warns this may reflect drug-induced microscopic colitis and states diarrhea "may be associated with weight loss, dehydration, and hypokalemia." Nausea (14% vs 8%), abdominal pain (8% vs 4%), and vomiting (4% vs 1%) were also more common than placebo.FDA-approved structured product label, entacapone, Adverse Reactions / Warnings (via openFDA)
All references used above
  1. Entacapone, FDA-approved structured product label — Clinical Pharmacology, Drug Interactions, Adverse Reactions, and Warnings sections, retrieved via the openFDA structured drug-label endpoint (api.fda.gov/drug/label.json); DailyMed's own web interface was blocked this session (see access note below)
  2. WHO Collaborating Centre for Drug Statistics Methodology, ATC/DDD Index — N04BX02, entacapone; DDD 1 g, oral
  3. Drugs.com consumer monograph for entacapone — Consumer reference, Tier D for grading purposes; used only to check for circulating consumer nutrient-depletion claims (none found) and not cited as primary evidence for any grade
  4. Orama M, Hannonen J, Taskinen J, et al. Iron(III)-chelating properties of the novel catechol O-methyltransferase inhibitor entacapone in aqueous solution. J Pharm Sci. 1997. PMID 9232524. — Physicochemical study characterizing entacapone's Fe(III)-chelation behavior in solution
  5. Pereira FC, Cheng JX, Wagner M, et al. The Parkinson's disease drug entacapone disrupts gut microbiome homeostasis via iron sequestration. Nat Microbiol. 2024;9(12):3165-3183. PMID 39572788. — Ex vivo human fecal-community study: quantitative microbiome profiling, long-read metagenomics, stable isotope probing, single-cell chemical imaging
  6. Guantai et al. Taxonomic and mechanistic insights into gut microbiota bioaccumulation of entacapone using bioorthogonal drug labelling. Microbiome Res Rep. 2025. DOI 10.20517/mrr.2025.73. — Ex vivo study, alkyne-tagged entacapone, FACS, 16S rRNA sequencing, donor fecal communities and E. coli strains
  7. Zesiewicz TA, Wecker L, Sullivan KL, Tatum WO, Baker MM. The controversy concerning plasma homocysteine in Parkinson disease patients treated with levodopa alone or with entacapone: effects of vitamin status. 2006. PMID 16772808. — Review article Access note: full abstract reconstructed via OpenAlex; original journal name not independently re-confirmed this session beyond the OpenAlex record.Access note: full abstract reconstructed via OpenAlex; original journal name not independently re-confirmed this session beyond the OpenAlex record.
  8. Zhao P, Yang JF, Liu W, Wang Y, Sun YN, Li Q, Zhang W, Zhang BS. Effects of entacapone on plasma homocysteine in Parkinson's disease patients on levodopa. Zhonghua Yi Xue Za Zhi. 2013. PMID 23660319. — Cross-sectional study, n=240 total (98 with MTHFR 677 CC genotype further stratified into 4 groups of 60); quantitative homocysteine by group: levodopa+entacapone approximately 15.1 micromol/L, levodopa alone approximately 20.4 micromol/L, healthy control approximately 9.1 micromol/L
  9. Valkovic P, Benetin J, Blazicek P, Valkovic L, Gmitterova K, Kukumberg P. Reduced plasma homocysteine levels in levodopa/entacapone treated Parkinson patients. Parkinsonism Relat Disord. 2005. PMID 15878587. DOI 10.1016/j.parkreldis.2005.01.007. — Title, authorship, journal, and year confirmed via OpenAlex Access note: full abstract text not retrieved this session (abstract_inverted_index unavailable via OpenAlex; PubMed abstract page access was rate-limited on every attempt this session). Cited for title-level direction only; quantitative results not independently verified.Access note: full abstract text not retrieved this session (abstract_inverted_index unavailable via OpenAlex; PubMed abstract page access was rate-limited on every attempt this session). Cited for title-level direction only; quantitative results not independently verified.
  10. Kocer B, Guven H, Comoglu SS. Homocysteine Levels in Parkinson's Disease: Is Entacapone Effective? Biomed Res Int. 2016. PMID 27493964. — Cross-sectional study, n=100, 3 arms (levodopa+dopamine agonist; levodopa+entacapone+dopamine agonist; dopamine agonist alone); serum B12, folate, and homocysteine measured in all patients; homocysteine elevated above normal in both levodopa-containing arms, not in the agonist-only arm; authors concluded entacapone "does not effectively prevent hyperhomocysteinemia"
  11. Di Rocco A, Werner P. Vitamins and entacapone in levodopa-induced hyperhomocysteinemia: a randomized controlled study. Neurology. 2007;68(17):1440-1441. PMID 17452598. — Randomized controlled trial, 3 arms (folate+B12; entacapone; control); folate+B12, not entacapone, reduced levodopa-induced homocysteine elevation; authors noted uncertainty whether the observation window was long enough to detect a slower entacapone effect
  12. Anamnart C, Kitjarak R. Effects of vitamin B12, folate, and entacapone on homocysteine levels in levodopa-treated Parkinson's disease patients. J Clin Neurosci. 2021;88:226-231. PMID 33992189. — Randomized controlled trial Access note: title, authorship, journal, year, and PMID confirmed; full abstract text not independently retrieved this session despite repeated attempts (OpenAlex abstract_inverted_index unavailable; PubMed abstract page access rate-limited).Access note: title, authorship, journal, year, and PMID confirmed; full abstract text not independently retrieved this session despite repeated attempts (OpenAlex abstract_inverted_index unavailable; PubMed abstract page access rate-limited).
  13. Ostrem JL, Kang GA, Subramanian I, Guarnieri M, Hubble JP, Rabinowicz AL, Bronstein JM. The effect of entacapone on homocysteine levels in Parkinson disease. Neurology. 2005;64(8):1482. PMID 15851757. — Short report Access note: title, authorship, journal/volume/issue/page, and PMID confirmed via OpenAlex; full abstract text not independently retrieved this session (OpenAlex abstract_inverted_index unavailable; multiple PubMed abstract-page fetch attempts returned 429 rate-limit errors).Access note: title, authorship, journal/volume/issue/page, and PMID confirmed via OpenAlex; full abstract text not independently retrieved this session (OpenAlex abstract_inverted_index unavailable; multiple PubMed abstract-page fetch attempts returned 429 rate-limit errors).
  14. Nevrly M, Kanovsky P, Vranova H, Langova K, Hlustik P. Effect of entacapone on plasma homocysteine levels in Parkinson's disease patients. Neurol Sci. 2010. PMID 20464572. — Access note: title, authorship, journal, and year confirmed via OpenAlex; full abstract text not independently retrieved this session (abstract_inverted_index unavailable via OpenAlex).Access note: title, authorship, journal, and year confirmed via OpenAlex; full abstract text not independently retrieved this session (abstract_inverted_index unavailable via OpenAlex).
  15. Grofik M, Sivak S, Nosal V, Turcanova Koprusakova M, Michalik J, Cierny D, Tatarkova Z, Kurca E. The influence of levodopa, entacapone and homocysteine on prevalence of polyneuropathy in patients with Parkinson's disease. J Neurol Sci. 2018. PMID 30097148. — Observational/case-control study; examines a clinical outcome (polyneuropathy prevalence), cited here as outcome context under the Vitamin B12/folate/B6 entry, not graded as a deficiency per Hard Rule 2 Access note: title, authorship, journal, and year confirmed via OpenAlex; full abstract text not independently retrieved this session.Access note: title, authorship, journal, and year confirmed via OpenAlex; full abstract text not independently retrieved this session.
  16. Haasio K, Lounatmaa K, Sukura A. Entacapone does not induce conformational changes in liver mitochondria or skeletal muscle in vivo. Exp Toxicol Pathol. 2002;54(1):9-14. PMID 12180806. DOI 10.1078/0940-2993-00228. — Animal study, Sprague-Dawley rats, electron microscopy of liver mitochondria and skeletal muscle, 2,4-dinitrophenol used as a positive uncoupling control; authored by Orion Pharma researchers (entacapone's originator) and university collaborators
  17. Nissinen E, Kaheinen P, Penttila KE, Kaivola J, Linden IB. Entacapone, a novel catechol-O-methyltransferase inhibitor for Parkinson's disease, does not impair mitochondrial energy production. Eur J Pharmacol. 1997. PMID 9537825. DOI 10.1016/s0014-2999(97)01431-3. — Mitochondrial/energy-production mechanistic study Access note: title, authorship, journal, and PMID confirmed via OpenAlex; full abstract text not independently retrieved this session (abstract_inverted_index unavailable).Access note: title, authorship, journal, and PMID confirmed via OpenAlex; full abstract text not independently retrieved this session (abstract_inverted_index unavailable).
  18. Grunig D, Felser A, Bouitbir J, Krahenbuhl S. The catechol-O-methyltransferase inhibitors tolcapone and entacapone uncouple and inhibit the mitochondrial respiratory chain in HepaRG cells. Toxicol In Vitro. 2017. PMID 28526448. DOI 10.1016/j.tiv.2017.05.013. — In vitro study, human HepaRG hepatocyte-like cells plus isolated mouse liver mitochondria; tolcapone tested up to 333 micromol/L (cytotoxicity IC50), entacapone up to 200 micromol/L (no cytotoxicity/ATP depletion observed); tolcapone ATP-depletion IC50 approximately 100 micromol/L and inhibited respiratory complexes I, II, IV; both compounds uncoupled oxidative phosphorylation in isolated mitochondria, tolcapone more potently
  19. Haasio K, et al. Effects of entacapone and tolcapone on mitochondrial membrane potential. Eur J Pharmacol. 2002. PMID 12393055. — Mitochondrial membrane-potential mechanistic study Access note: title, authors, journal, year, and PMID confirmed via PubMed search-listing page only; full abstract not independently retrieved this session.Access note: title, authors, journal, year, and PMID confirmed via PubMed search-listing page only; full abstract not independently retrieved this session.
  20. Pinto M, et al. Cellular and Mitochondrial Toxicity of Tolcapone, Entacapone, and New Nitrocatechol Derivatives. ACS Pharmacol Transl Sci. 2024. PMID 38751615. — Comparative cellular/mitochondrial toxicity study Access note: title, journal, year, and PMID confirmed via PubMed search-listing page only; full abstract not independently retrieved this session.Access note: title, journal, year, and PMID confirmed via PubMed search-listing page only; full abstract not independently retrieved this session.
  21. Grunig D, et al. Effect of the Catechol-O-Methyltransferase Inhibitors Tolcapone and Entacapone on Fatty Acid Metabolism in HepaRG Cells. Toxicol Sci. 2018. PMID 29688484. — In vitro metabolic study Access note: title, journal, year, and PMID confirmed via PubMed search-listing page only; full abstract not independently retrieved this session.Access note: title, journal, year, and PMID confirmed via PubMed search-listing page only; full abstract not independently retrieved this session.
  22. Chen AY, Lu JM, Yao QC, Chen C. Entacapone is an Antioxidant More Potent than Vitamin C and Vitamin E for Scavenging of Hypochlorous Acid and Peroxynitrite, and the Inhibition of Oxidative Stress-Induced Cell Death. Med Sci Monit. 2016. PMID 26927838. DOI 10.12659/msm.896462. — In vitro study, human umbilical vein endothelial cells (HUVECs); entacapone 10-20 micromol/L scavenged 60-83% of DPPH radicals, approximately 8-fold stronger hypochlorous-acid scavenging and 8-30% stronger peroxynitrite scavenging than vitamin C
  23. Lyras L, Zeng BY, McKenzie G, Pearce RK, Halliwell B, Jenner P. Chronic high dose L-DOPA alone or in combination with the COMT inhibitor entacapone does not increase oxidative damage or impair the function of the nigrostriatal pathway in normal cynomolgus monkeys. J Neural Transm. 2002;109(1):53-67. PMID 11793162. — Animal study, cynomolgus monkeys (non-human primate); markers measured: lipid peroxidation, protein carbonyls, oxidative DNA damage, tyrosine hydroxylase expression/function
  24. Yang J, et al. Entacapone alleviates acute kidney injury by inhibiting ferroptosis. FASEB J. 2022. PMID 35691001. — Protective/reverse-direction finding (anti-ferroptosis in an acute-kidney-injury model), cited as context only and not graded as a separate entry per Hard Rule 2 (this is a therapeutic/protective pharmacology finding in an unrelated disease model, not a nutrient-deficiency claim) Access note: title, journal, year, and PMID confirmed via PubMed search-listing page only; full abstract not independently retrieved this session.Access note: title, journal, year, and PMID confirmed via PubMed search-listing page only; full abstract not independently retrieved this session.