Plecanatide

guanylate cyclase-C (GC-C) agonist, intestinal secretagogue (uroguanylin analog)

Also sold as Trulance.

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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.

Plecanatide has no systemic depletion machinery. The US label states it was "minimally absorbed with negligible systemic availability," that AUC, Cmax and half-life "could not be calculated," that it is metabolized inside the gut to an active metabolite by loss of the terminal leucine and then degraded to small peptides and amino acids, and that in vitro neither the drug nor the metabolite inhibited CYP2C9 or CYP3A4 or acted as a P-gp or BCRP substrate or inhibitor [1]. The FDA clinical pharmacology review adds that plasma levels were below the limit of quantification even at doses up to 9 mg, three times the labeled dose [5], and a 2025 phase III trial in China reported the same below-quantification result [6]. Hepatic enzyme induction, renal wasting, cofactor antagonism, mitochondrial interference and conjugation-driven loss are therefore not expected, and nothing retrieved supports any of them. The only mechanisms present are local to the intestine: GC-C activation raises cGMP and increases chloride and bicarbonate secretion with water, which accelerates transit [1].

guanylate cyclase-C (GC-C) agonist, intestinal secretagogue (uroguanylin analog) · ATC A06AX07 (WHO ATC/DDD Index [2]) · also sold as Trulance (US label [1]) · reviewed 2026-10-04. 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 Plecanatide 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

Fluid and electrolytes: disturbance from diarrhea (boxed pediatric dehydration warning), not a dietary deficiency

Yellow — Low

See study details

Plecanatide's intended fluid-secretory effect causes diarrhea in roughly 4 to 5% of adult trial participants (about 1% severe at most), carries a boxed warning for fatal dehydration in young juvenile mice, and is associated with water and electrolyte disorder signals in spontaneous reports; this is a loss-and-disturbance outcome of the drug's own pharmacology, not a nutrient deficiency.

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

Limits on what this shows

Null findings: FDA summary review [3]: severe diarrhea 0.6% vs 0.3%; the review "does not report similar findings for plecanatide in clinical trials" to the linaclotide hypokalemia and syncope reports. FDA medical review [4], as returned by the fetch tool: no incidence figures found for hypokalemia, hyponatremia, dehydration, decreased blood potassium, anemia or hemoglobin decrease in plecanatide-treated patients versus placebo, and "no signals of UPD-related AEs (hypertension, edema, pulmonary edema, hypernatremia, weight gain)" (the abbreviation UPD was not expanded in the extraction I received). The 2019 Drug Safety benefit-risk review [7] (abstract only) gave no diarrhea, electrolyte or hematology data in the text accessible to me. Laboratory tables in that review itemized liver enzymes and bilirubin; serum electrolyte and hematology shifts were not itemized in the excerpts returned, so this is an absence of reporting, not a measured null.
At-risk subgroups: Children under 6 (contraindicated) and ages 6 to under 18 (avoid) [1]; anyone with severe or persistent diarrhea. Co-prescribed diuretics, vomiting (a labeled postmarketing report) and poor oral intake are general clinical contexts that raise risk for any diarrheal illness; they are not plecanatide findings.

Regulatory status

Boxed warning: contraindicated under 6 years because single oral doses caused deaths from dehydration in young juvenile mice. Section 5.1: avoid ages 6 to under 18. Section 5.2: if severe diarrhea occurs, suspend dosing and rehydrate. Section 6.2 (postmarketing) lists hypersensitivity reactions and vomiting; in the sections retrieved the label does not list hypokalemia, hyponatremia or other electrolyte abnormalities, and a term search reported that "electrolyte" does not occur and "bicarbonate" occurs only in the mechanism of action [1] (text via summarizing fetch). The linaclotide label, by contrast, names hypokalemia and hyponatremia; that language is quoted in the FDA plecanatide summary review as context [3] and is not borrowed here.

Population evidence

Label trials [1]: CIC (N=1,733) diarrhea 5% vs 1% placebo, severe diarrhea 0.6% vs 0.3%; IBS-C (N=1,449) diarrhea 4.3% vs 1%, severe 1% vs 0.1%. FDA summary review [3] repeats the severe diarrhea figure of 0.6% vs 0.3% and states the juvenile mouse deaths occurred at 0.5 mg/kg on postnatal day 7 and 10 mg/kg on day 14, with none in older juvenile or adult animals. Phase III trial in China [6] (N=648, plecanatide 3 mg vs placebo, 12 weeks, 40 hospitals): diarrhea 4.3% vs 0.6% (p=0.002); the fetch extraction reported no electrolyte or hemoglobin laboratory abnormalities in the text provided, which is not the same as a documented null. FAERS analysis [8] (Hospital Pharmacy 2025, abstract only): 12,275 linaclotide and 811 plecanatide reports from Q1 2013 to Q4 2023, disproportionality signals by ROR and PRR (2,230 signals for plecanatide), and the statement that both drugs "revealed signals related to water and electrolyte disorders"; specific terms, counts and plecanatide-only values were not accessible. A second FAERS analysis [9] (abstract only) reported diarrhea in 20.4% (n=137) of plecanatide reports in IBS-C, a share of spontaneous reports and not an incidence, and linked dehydration concern to linaclotide, not plecanatide.

Mechanism

Present and labeled. GC-C activation raises cGMP and increases chloride and bicarbonate secretion with accompanying sodium and water, which softens stool and speeds transit [1 sec 12.1]. Fluid and electrolyte loss in stool is the intended effect carried to excess. No systemic or renal mechanism exists because the drug is not absorbed [1][5]. Whether luminal bicarbonate secretion alters serum bicarbonate was not measured in anything retrieved and is not claimed.

Class cohort test

Not a class extrapolation. Plecanatide was named in the cohort of [1], [3], [4], [6], [8] and [9]. No linaclotide label or trial result was used to support the grade.

Counter-evidence held on record

Counter-evidence and confounding The spontaneous-report signals cannot give incidence or prove causation, are subject to notoriety and reporting bias, and the pooled abstract does not separate plecanatide from linaclotide [8]. The adult trial rates of severe diarrhea were 1% or lower [1]. The label itself lists no electrolyte abnormality for plecanatide. Framing caution This is a loss-and-disturbance effect of the drug's intended action, not a deficiency, and it must not be read as advice to increase potassium or sodium intake or to take supplements. The labeled response is to stop the drug and rehydrate under clinical guidance. No supplement dose is given here.

Micronutrient absorption via faster transit (nonspecific)

Not graded — disclosed evidence gap

See study details

Accelerated transit and diarrhea could in principle shorten nutrient contact time, but no vitamin, mineral or fat-soluble nutrient was named or measured for plecanatide in anything retrieved.

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: Dual condition met: no Tier B or C study (a mechanism reasoned from first principles is not a study with this drug) and no circulating claim located. Not a finding of safety and not a deficiency signal. Overlaps the fluid and electrolytes entry on mechanism only.

What was searched

PubMed listing for vitamin, nutrient, malabsorption, oxalate, magnesium and zinc terms [13]: 4 records, none a plecanatide nutrient study. Label [1]: no malabsorption, nutrient, vitamin or mineral term; section 7 omitted. Drugs.com side effects [14] and interaction page [16]: no malabsorption, vitamin or mineral item. Mechanism class A (altered transit time) is present in the drug's pharmacology [1 sec 12.1], so the item was carried forward and tested rather than skipped. A linaclotide-titled 2023 abstract on oxalate nephropathy appeared in the sibling linaclotide dossier; the "oxalate" term in the plecanatide PubMed query returned no plecanatide oxalate record. Repair pass: the plecanatide FAERS analysis [18] did not report malabsorption, vitamin deficiency or weight decreased among its signals as returned by the fetch tool (not highlighted, not a zero count), while it did list diarrhea (275 cases) and abdominal distension; the 2017 label [22] has no section 7; the FDA cross-discipline review [23] notes treatment-related increases in the weight of intestinal contents in juvenile mice and no nutrient absorption data.

Channel outcomes

One earlier PubMed attempt with the same terms returned 429 and a second, with magnesium and zinc added, succeeded. Others as for Mitochondrial burden.

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

Not graded — disclosed evidence gap

See study details

No plecanatide-specific evidence on mitochondrial structure, electron transport or biogenesis was retrieved, and the drug's lack of systemic exposure makes a direct effect implausible.

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: Dual condition met: no Tier B or C source supports even a yellow grade, and no circulating consumer claim of plecanatide mitochondrial damage was found to rebut. Classification: probably a genuine gap (the label, three FDA reviews, two plecanatide mouse studies that did not measure it, and a PubMed listing agree), but tooling-limited in that Europe PMC, Semantic Scholar, OpenAlex search and Crossref search could not be used. This is not a finding of safety.

What was searched

PubMed listing "plecanatide AND (oxidative OR mitochondria OR mitochondrial OR ATP OR antioxidant OR ROS)" [11]: 6 records, by title two clinical practice guideline copies, a pediatric constipation meta-analysis, a 2024 J Biol Chem paper on receptor guanylyl cyclase C evolutionary divergence, a nursing drug digest and a chromatography paper; none concerns mitochondria in plecanatide users (titles only, abstracts not opened). US label [1] term search: mitochondria, ATP, oxidative and antioxidant do not occur. FDA clinical pharmacology review [5]: no mitochondrial or oxidative findings reported. FDA summary review [3]: topic not addressed. Tier D Drugs.com pages [14][15][16]: no mitochondrial claim. Repair pass: web search for plecanatide with mitochondria, oxidative stress, iron and hemoglobin terms returned only unrelated iron-overload and ferroptosis papers (none with plecanatide). Opened the plecanatide and dolcanatide murine colitis study [19] (BALB/c, BDF1 and TCRa-/- mice; plecanatide and dolcanatide 0.005 to 5.0 mg/kg by gavage; TNBS, DSS and spontaneous colitis models) and the plecanatide Apc+/Min-FCCC mouse study [20] (n=92; DSS plus 2, 10 or 20 ppm plecanatide in diet, or 2.5 mg/kg gavage): neither reports a mitochondrial or ATP endpoint. The FDA cross-discipline review [23] reports no mitochondrial data.

Channel outcomes

Repair pass: WebSearch worked for nine queries, then the session budget was exhausted; an OpenAlex search-endpoint query and a PubMed iron/anemia/hemoglobin listing returned 429 again, and the fetch tool asked that they not be retried. Original pass: PubMed listing: worked for this query. OpenAlex search endpoint: 429 (two attempts, different queries). Crossref search: 429 with a fetch-tool instruction not to refetch. Europe PMC REST: 429. Semantic Scholar search: 429. NCBI PMC search: refused by robots.txt. Web search: session budget exhausted (200 of 200). Direct database APIs were not used, per the environment policy.

Oxidative Stress

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

Oxidative stress

Not graded — disclosed evidence gap

See study details

No evidence was retrieved that plecanatide raises or lowers systemic or tissue redox markers or antioxidant capacity.

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: Dual condition met: no Tier B or C evidence and no circulating oxidative stress or antioxidant-depletion claim for plecanatide found. Tooling-limited, probably thin literature. Not a finding of safety.

What was searched

The combined PubMed listing above [11] included the terms oxidative, antioxidant and ROS and returned no plecanatide redox study by title. Label [1] and FDA reviews [3][5] contain no oxidative or antioxidant statement. The OpenAlex-reconstructed abstract of a 2018 Frontiers in Oncology review of GC-C signaling [10] describes epithelial injury, DNA damage responses and metabolic status as GUCY2C-regulated and names plecanatide only as one of several synthetic ligands; it is a narrative review of receptor biology with no plecanatide-treated cohort and no redox marker named in the abstract, and it is not used. Repair pass: the only redox-adjacent measurement found in a plecanatide-named study is colonic myeloperoxidase (MPO, a neutrophil-infiltration enzyme and an inflammation marker, not an antioxidant-capacity or redox-balance marker) in the murine colitis paper [19]; that paper states MPO fell with 5-ASA and with dolcanatide in the DSS model, and plecanatide was not evaluated for MPO, so it is not a plecanatide result and not used. The Apc+/Min-FCCC study [20] reports cytokines, cGMP, body weight and caspase-3, and no redox marker. Dolcanatide is a different molecule and was not borrowed. Surrogate terms (ROS, antioxidant) were part of the listing; malondialdehyde and antioxidant enzyme terms were not run separately because of rate limiting.

Channel outcomes

As for Mitochondrial burden (repair pass included the two mouse papers [19][20], opened through summarizing fetch with targeted term queries).

Copper and Iron Balance

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

Copper

Not graded — disclosed evidence gap

See study details

No evidence was retrieved on plecanatide and copper status, absorption or chelation.

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: Dual condition met: no Tier B or C source (no chelation study, no human measurement) and no circulating copper claim found. Tooling-limited. Kept independent of Iron per Hard Rule 7. Not a finding of safety.

What was searched

PubMed listing "plecanatide AND (iron OR anemia OR hemoglobin OR copper OR ferritin)" returned a 404 page, and the simpler "plecanatide anemia" also returned 404; the listings that did return results returned HTTP 200, so these 404s are probably the PubMed response for zero hits, but that is an inference I could not confirm. PubMed listing "plecanatide AND (vitamin OR nutrient OR malabsorption OR oxalate OR magnesium OR zinc)" [13]: 4 records, two guideline copies, a pediatric meta-analysis and a CKD constipation review, none a nutrient study of plecanatide. Label [1] term search: copper, mineral, vitamin and nutrient do not occur. Label section 7 (drug interactions) is omitted. Drugs.com interaction page [16] lists no food, vitamin, mineral or supplement interaction. The product is a peptide with no metal-binding statement in anything retrieved. Repair pass: the 2017 US label PDF [22] has no section 7 and no mineral or copper text; its nonclinical section 13.1 reports no tumorigenicity in 2-year mouse (to 90 mg/kg/day) and rat (to 100 mg/kg/day) studies and negative genotoxicity, with no mineral or hematology findings; the FDA cross-discipline review [23] contains no repeat-dose hematology, iron or mineral findings. Plecanatide FAERS analysis [18] (861 reports): no copper-related, vitamin or malabsorption term was reported among the signals shown.

Channel outcomes

As for Mitochondrial burden; plus the two 404 PubMed listings noted above. A repair-pass web search combining plecanatide with vitamin, iron, ferritin, B12 and malabsorption terms returned only unrelated anemia pages.

Iron

Not graded — disclosed evidence gap

See study details

No evidence was retrieved that plecanatide alters iron absorption, stores or iron deficiency risk.

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: Dual condition met: no Tier B or C evidence and no circulating iron claim for plecanatide located. Because the label, two FDA reviews, a phase III report and two PubMed listings all return nothing, a genuine thin-literature gap is likely, though the search-engine channels were rate limited. Kept independent of Copper per Hard Rule 7. Not a finding of safety. Anemia would not be iron deficiency in any case (Hard Rule 2).

What was searched

PubMed listings with iron, anemia, hemoglobin and ferritin terms: both returned 404 (see Copper for the interpretation caveat). Label [1] term search: iron, anemia and hemoglobin do not occur; the label's laboratory-relevant adverse reaction is increased liver enzymes (ALT/AST). FDA medical review [4], as returned by the fetch tool: no incidence figures for anemia or decreased hemoglobin; hematology shifts were not itemized in the excerpts returned. FDA summary review [3]: hematology topics not addressed. Chinese phase III [6]: no hemoglobin laboratory abnormality reported in the text provided. Tier D Drugs.com side effect list [14]: no anemia and no iron item. Tier D interaction page [16]: no iron interaction. Repair pass: the plecanatide FAERS analysis [18] (861 reports, 2,057 events, Q1 2017 to Q2 2024), as returned by the fetch tool, did not report anaemia, haemoglobin decreased or iron deficiency among the signals shown (the extraction describes them as not highlighted in the tables or discussion, which is not the same as a documented zero count). The integrated IBS-C analysis [21] (2,182 in the safety population) states that clinical laboratory tests were monitored but reports no laboratory results in the text retrieved. The 2017 label [22] section 6.1 lists only ALT and AST elevations. The FDA cross-discipline review [23] reports no hematology parameters in the trials and no repeat-dose hematology in the nonclinical studies. The Apc+/Min-FCCC mouse study [20] did not address iron, hemoglobin or anemia.

Channel outcomes

PubMed iron listings: 404 twice in the original pass; a repair-pass PubMed listing with anemia, hemoglobin and iron terms returned 429 and was not retried. Others as for Mitochondrial burden. The FDA medical review is a large document and the extraction I received was a search summary, so a hematology table could exist that I did not see.

Gut Microbiome Risk

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

Gut microbiome risk

Not graded — disclosed evidence gap

See study details

No study measured the gut microbiome in people or animals given plecanatide, and no plecanatide-named class extrapolation passes the cohort test.

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: Dual condition met: no Tier B or C source with plecanatide in the cohort, and no circulating claim that plecanatide disrupts the microbiome was found. Tooling-limited for the full literature, but the PubMed listing returned only reviews, which points to a genuine gap. This is not a finding of safety. Mechanistically, luminal fluid secretion and faster transit could shift fecal communities, but that is reasoning, not a study with this drug.

What was searched

PubMed listing "plecanatide AND (microbiome OR microbiota OR dysbiosis)" [12]: 5 records, all reviews by title (constipation in CKD, new IBS treatments in Nat Rev Gastroenterol Hepatol, constipation-predominant IBS pharmacotherapies, advancing CIC treatment options, and the GC-C signaling review in Frontiers in Oncology). None is a plecanatide microbiome measurement. Two were opened as OpenAlex-reconstructed abstracts: the CKD constipation review [17] mentions "altered gut microbiota" only as a cause of constipation and says linaclotide and plecanatide have very limited systemic absorption; the GC-C signaling review [10] states that GUCY2C signaling "regulates fluid secretion, microbiome composition, barrier integrity" on the basis of mouse models and human studies, and names plecanatide only as a synthetic ligand. Label [1], FDA reviews [3][4][5] and the Springer page of the Chinese phase III [6] contain no microbiome statement. The Drugs.com pages [14][15] contain none. Repair pass: a web search for plecanatide with colitis, microbiota, 16S and dysbiosis terms surfaced the two plecanatide mouse studies [19][20], neither of which reports microbiome composition (the colitis paper [19] mentions gut flora only as a general caveat about diet and husbandry; the Apc+/Min-FCCC paper [20] does not address it), and the FDA cross-discipline review [23] has no microbiome content. A search result also showed a PubMed record titled "Guanylate Cyclase C Activation Shapes the Intestinal Microbiota in Patients with Familial Diarrhea and Increased Susceptibility for Crohn's Disease" (PMID 28902124); the PubMed page returned 429 and was not opened, so no content is cited. By its title the cohort is patients with a GUCY2C activating mutation, a genetic model of GC-C overactivation, not plecanatide users; it would fail the cohort test and, as class or mechanism extrapolation, could at most support a yellow, so it is recorded here and not graded.

Cohort test (class extrapolation considered, rejected)

CLASS EXTRAPOLATION candidates were examined and not used. (a) The linaclotide microbiome pre-post study (Zhou 2024, identified in the sibling linaclotide dossier; I did not open it in this session): linaclotide only, plecanatide NOT in the cohort, so it fails and is not cited as a source. (b) The Frontiers review [10]: a narrative review of receptor biology, plecanatide named only as an available ligand, no plecanatide-treated cohort, so it fails. Had a plecanatide-named cohort existed, the ceiling would have been yellow. Editors who read [10] as Tier C context could argue for a yellow, but it would not be a drug-level finding and would rest on a mouse-genetics statement the abstract does not tie to plecanatide.

Channel outcomes

PubMed listing worked. Crossref, OpenAlex search, Europe PMC REST and Semantic Scholar returned 429. Repair pass: WebSearch worked for several microbiota phrasings (one returned only unrelated fecal-transplant papers); PubMed record 28902124 returned 429 and was not opened; the web search budget was then exhausted. Titles only were seen for the three reviews not opened.

Oxygen and ATP Output

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

Oxygen delivery/utilization

Not graded — disclosed evidence gap

See study details

No evidence was found that plecanatide reduces hemoglobin, red-cell mass or tissue oxygen delivery by any route.

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: Dual condition met: no Tier B or C evidence and no circulating oxygen-carrying claim found. Genuine gap plausible given zero systemic exposure, but not confirmed. Kept independent of ATP production and Mitochondrial burden. Volume depletion from diarrhea (see the fluid and electrolytes entry) is a fluid outcome, not an oxygen-delivery deficiency (Hard Rule 2).

What was searched

The same iron, anemia and hemoglobin PubMed listings (404 twice), the label [1] (no hematologic adverse reaction in the sections retrieved; hemoglobin and anemia do not occur), FDA medical review [4] (no anemia or hemoglobin-decrease incidence figures found) and Chinese phase III [6] (no hemoglobin abnormality in the text provided). Methemoglobin and hemolysis surrogate terms were not run as separate queries because of rate limiting, and the label term search I received did not specifically test for them, so that part is untested. Repair pass added: plecanatide FAERS analysis [18] did not report anaemia or haemoglobin decreased among its signals (extraction wording: not highlighted, not a zero count); integrated IBS-C analysis [21] reports no hematology results; FDA cross-discipline review [23] reports no hemoglobin or hematology parameters in the trials and no repeat-dose nonclinical hematology. Methemoglobin and hemolysis terms were still not run as separate queries because the search budget was exhausted.

Channel outcomes

As for Iron.

ATP production

Not graded — disclosed evidence gap

See study details

No evidence was retrieved on plecanatide and cellular ATP synthesis or energy output.

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: Dual condition met: no Tier B or C evidence and no circulating "low energy" claim specific to plecanatide located. Not a finding of safety. Kept independent of Mitochondrial burden and Oxygen delivery/utilization even though all three share one search outcome (see Overlap map).

What was searched

The ATP term was part of the combined PubMed listing [11], which returned nothing on energy metabolism in plecanatide users by title. ATP does not occur in the label [1]; the FDA clinical pharmacology review [5] reports no mitochondrial or oxidative findings. Surrogate terms for respiration and oxidative phosphorylation were not run separately because PubMed then rate limited. Repair pass: the mouse studies [19][20] and the FDA cross-discipline review [23] contain no ATP, respiration or energy-metabolism endpoint. The plecanatide FAERS analysis [18] did not list fatigue or asthenia among its signals (extraction wording: not highlighted); this is a report-level observation, not an energy-metabolism measurement.

Channel outcomes

As for Mitochondrial burden. Tooling-limited.

Claims checked and not supported

These circulate online for this medication. They are listed here only so they can be answered, never as findings, and they are not graded.

A claim with no supporting evidence is not necessarily disproven. Where evidence actually argues against a claim, that is stated below.

No white entries identified
Where it comes from: No plecanatide-specific nutrient, mitochondrial, oxidative stress, copper, iron, microbiome, oxygen-carrying or "low energy" depletion claim was located. The Tier D Drugs.com side effect list [14] and patient monograph [15] list dehydration (animal studies, pediatric warning), diarrhea and other GI effects, and no depletion claim; the Drugs.com interaction page [16] lists no food, vitamin or mineral interaction.
Why it fails: Nothing to rebut from sources actually opened. This is tooling-limited: the web search budget was exhausted, so consumer depletion lists and supplement-retailer pages could not be surveyed broadly. A claim that plecanatide "depletes" nutrients the way some consumer lists describe stimulant laxatives was not found for this drug and was not borrowed from other laxatives or from linaclotide. Repair pass: two further consumer-claim searches (nutrient depletion; fatigue, low energy, mitochondrial damage) could not run because the web search budget was exhausted; the audit remains incomplete. Re-run the circulating-claim audit when web search is available.

How the body handles this medication

Absorption and systemic exposure: Minimally absorbed; negligible systemic availability. AUC, Cmax and half-life could not be calculated. Plasma plecanatide and its active metabolite SP-338 were below the limit of quantification (1.0 ng/mL and 0.775 ng/mL) at all clinical doses up to 9 mg in the FDA review; the 2025 Chinese phase III trial reported concentrations below 0.500 ng/mL at all time points. Little to no binding to human serum albumin; minimal tissue distribution expected.[1] sec 12.3; [5]; [6] (all via summarizing fetch)
Metabolism and enzymes: Metabolized in the GI tract to an active metabolite (SP-338) by loss of the terminal leucine; parent and metabolite are proteolytically degraded in the lumen to smaller peptides and naturally occurring amino acids. In vitro, neither inhibited CYP2C9 or CYP3A4, and neither was a P-gp or BCRP substrate or inhibitor; the FDA review also states plecanatide is not likely to induce CYP3A4 and that CYP metabolism in intestinal microsomes was not evaluated.[1] sec 12.3; [5]
Elimination: The label states no excretion studies have been conducted in humans; the FDA review gives no quantitative fecal recovery. Fecal elimination of degraded peptide is implied by the local mechanism but is not documented as a number.[1] sec 12.3; [5]
Renal and hepatic impairment: The label does not address renal or hepatic impairment dosing (section 8.6 not present in the text retrieved) and the drug interactions section is omitted. The FDA review judged a hepatic impairment study unnecessary because of no appreciable plasma absorption.[1] sec 7, 8.6; [5]
Local mechanism, food, mineral interactions: GC-C agonism raises cGMP and increases chloride and bicarbonate secretion into the lumen, with sodium and water following. Dose is 3 mg once daily, with or without food; tablets may be crushed in water or applesauce. In a pharmacodynamic study subjects given a low-fat or high-fat meal reported looser stools than fasted subjects for up to 24 hours. No vitamin, mineral or antacid interaction is listed in the label text retrieved or on the Tier D interaction page [16].[1] sec 2, 12.1, 12.2; [5]
Fluid effect, pediatrics, pregnancy: Boxed warning: contraindicated under 6 years because single oral doses caused deaths from dehydration in young juvenile mice; section 5.1: avoid in ages 6 to under 18. Severe diarrhea: suspend dosing and rehydrate. Pregnancy: no fetal exposure expected; no embryo-fetal harm in mice (to 800 mg/kg/day) or rabbits (to 250 mg/kg/day). Lactation: drug and metabolite not measurable in milk. Label revision text: 3/2024 (DailyMed record published Apr 05, 2024).[1] boxed warning, sec 5.1, 5.2, 8.1, 8.2, 8.4

What the research says is worth watching

General information from the medication label and the studies above. It is not personal medical advice, and any change belongs with your prescriber.

Clinical / dominant effect
Diarrhea and hydration
Severe diarrhea is the labeled reason to suspend dosing and rehydrate [1 sec 5.2]. Diarrhea was 4.3 to 5% on drug in label trials [1].
Lab / only if indicated
Serum potassium and sodium
Reasonable after severe or persistent diarrhea, vomiting, or when a diuretic is co-prescribed. This is general clinical practice for diarrheal illness; the plecanatide label does not require routine electrolyte monitoring [1]. A disturbance here is fluid loss, not a dietary shortfall.
Pediatrics
Children
Boxed warning: contraindicated under 6 years because of fatal dehydration in young juvenile mice; avoid at ages 6 to under 18 [1 sec 5.1, 8.4].
Pregnancy and lactation
Reproductive considerations
No fetal exposure expected; drug and metabolite not measurable in breast milk [1 sec 8.1, 8.2]. Dehydration from diarrhea remains a general pregnancy concern.
Renal / hepatic
Organ impairment
The label gives no dosing guidance for renal or hepatic impairment; the FDA review judged no study necessary because of no appreciable absorption [5]. Increased ALT/AST were reported in a small number of trial patients [1]. Dehydration risk applies to anyone with limited fluid reserve.
Timing
Meals and supplements
Taken once daily with or without food [1]. No vitamin, mineral or antacid separation interval is listed. No supplement dose is recommended or appears anywhere in this dossier, so no upper-limit comparison was needed.

Overlap map, to prevent double counting

All entries
Shares evidence with: Label [1]; FDA reviews [3][4][5]
Note: The label underlies the PK basis, the electrolyte entry and every statement that "the label lists no nutrient effect." The three FDA review documents are reviews of the same sponsor application and are read together with the label as one regulatory silence, not as independent confirmation in each ungraded entry.
Fluid and electrolytes
Shares evidence with: Micronutrient absorption via faster transit (ungraded)
Note: Same mechanism (GC-C-driven fluid secretion and accelerated transit [1]). Only the electrolyte disturbance has support; the absorption item has none and is not counted as a second signal.
Fluid and electrolytes
Shares evidence with: Two FAERS analyses [8][9]
Note: Both draw on the same FDA Adverse Event Reporting System database, with overlapping years, so they are one spontaneous-report source, not two independent confirmations.
Mitochondrial burden
Shares evidence with: Oxidative stress; ATP production; Oxygen delivery/utilization (all ungraded)
Note: The four are ungraded for the same reason: the same label silence and the same PubMed listing outcomes. One gap viewed four times, not four independent gaps.
Gut microbiome risk
Shares evidence with: Oxidative stress (ungraded)
Note: Both mention the Frontiers GC-C signaling review [10] as a considered and rejected source. It is not evidence for either entry.
Gut microbiome risk
Shares evidence with: Micronutrient absorption via faster transit (ungraded)
Note: No shared source. A microbiome shift is a hypothetical modifier of nutrient handling and is not claimed.
Iron; Oxygen delivery/utilization; ATP production; Micronutrient absorption (ungraded)
Shares evidence with: Plecanatide FAERS analysis [18]; FDA cross-discipline review [23]
Note: The same extraction of absent terms (anaemia, haemoglobin decreased, fatigue, malabsorption, vitamins) and the same laboratory silence is the null for all four; it is one source viewed several times. [18] also overlaps the Fluid and electrolytes entry's spontaneous-report source [8][9] because all three draw on the FDA Adverse Event Reporting System.
Mitochondrial burden; Oxidative stress; Gut microbiome risk
Shares evidence with: Plecanatide mouse studies [19][20]
Note: The same two mouse papers are the null for all three, as neither measured those endpoints. One null viewed three times.
Copper
Shares evidence with: Iron (ungraded)
Note: No shared source; the same 404 PubMed listings touched both. Graded separately per Hard Rule 7.
Iron
Shares evidence with: Oxygen delivery/utilization (ungraded)
Note: Both use the same PubMed listings, the FDA medical review excerpt [4] and the Chinese phase III text [6] as their null results. Any hematologic effect would run through iron, so oxygen delivery is not counted separately. Entries stay independent per Hard Rule 7.

All references used above

Plecanatide

Findings for this medication

What the research found

Fluid and electrolytes: disturbance from diarrhea (boxed pediatric dehydration warning), not a dietary deficiency

Micronutrient absorption via faster transit (nonspecific)

The five body-system areas

⚡Mitochondrial Burden

Mitochondrial burden

💥Oxidative Stress

Oxidative stress

⚖️Copper and Iron Balance

Copper

Iron

🌿Gut Microbiome Risk

Gut microbiome risk

💨Oxygen and ATP Output

Oxygen delivery/utilization

ATP production

Claims checked and not supported

No white entries identified

How the body handles this medication

What the research says is worth watching

Overlap map, to prevent double counting

Mitochondrial Burden

Oxidative Stress

Copper and Iron Balance

Gut Microbiome Risk

Oxygen and ATP Output