Rabeprazole

Limits on what this shows

• Null findings: PubMed listings for rabeprazole with mitochondria or mitochondrial returned a single unrelated item (a parasite glycolytic enzyme [32]); no rabeprazole mitochondrial-function study was found.
• At-risk subgroups: None identified.

Regulatory status

Not addressed. The label mechanism is covalent inhibition of the gastric (H+, K+)-ATPase, a proton pump distinct from mitochondrial machinery; that intended effect is not graded here (Hard Rule 2) [1].

Evidence (Tier C, class)

Sprague-Dawley rats with chronic kidney disease given omeprazole, esomeprazole or lansoprazole (rabeprazole not mentioned in the record): PPIs inhibited COX-2-mediated mitophagy through the PINK1/Parkin pathway in vascular smooth muscle and accelerated vascular calcification [27]. Rabeprazole was in the PPI set of the lysosome and ER-stress study [26], but its abstract addresses lysosomal and ER compartments and not mitochondria.

Mechanism

Impaired selective autophagy of mitochondria (mechanism E) in class-level animal data [27]; no rabeprazole mechanism located.

Counter-evidence held on record

Counter-evidence on record Abstract-level reading through OpenAlex; a CKD rat model with a vascular-calcification outcome does not predict mitochondrial effects in people taking rabeprazole, and the drug is not named in the record. Held at yellow only because the class-extrapolation rule is met (a class member has real supporting data). Framing caution No mitochondrial-support supplement is recommended. Shares evidence with Oxidative stress; see Overlap map.

Limits on what this shows

• Null findings: No human study measuring oxidative stress markers in rabeprazole users was located. The scavenging assay shows rabeprazole is the weakest of five PPIs tested [25].
• At-risk subgroups: None identified.

Regulatory status

Not addressed in the label text returned [1].

Evidence (Tier B, rabeprazole)

Male Wistar rats with acetic-acid colonic injury, rabeprazole 20 mg/kg/day for 10 days: malondialdehyde decreased, superoxide dismutase activity and glutathione increased, histology and inflammatory markers attenuated [24]. DPPH radical-scavenging assay: omeprazole and esomeprazole scavenged most (IC50 18.7 +/- 5.7 and 5.7 micromolar); rabeprazole showed minimal activity (IC50 49.3 +/- 3.1, 49 +/- 9.4 and 40.7 +/- 7.2 micromolar across measurements) [25]. Cell and organelle work including rabeprazole: PPIs at 20 micromolar suppressed about 70% of V-ATPase function in isolated lysosomes, caused TFEB nuclear translocation, ER stress through PERK, IRE1 and ATF6, and increased SOD activity; results reported for the PPIs together (esomeprazole, pantoprazole, dexlansoprazole, rabeprazole) [26].

Mechanism

Weak direct radical scavenging by rabeprazole [25]; indirect antioxidant-enzyme effects in an injury model [24]; lysosomal and ER stress with a compensatory SOD rise in cells [26]. Human relevance unproven.

Counter-evidence held on record

Counter-evidence on record The same drug looks protective in an injury model and stress-inducing in cells, and weakly antioxidant in chemistry, so no single direction can be attributed. [26] reports class-level results, and its 20 micromolar exposure was not compared with clinical plasma levels in the abstract. Doses in rats are not human-equivalent. Framing caution Mechanistic only; neither an antioxidant-depletion claim nor a benefit claim. No antioxidant supplement is recommended.

Limits on what this shows

• Null findings: No rabeprazole-specific null study was located. Class context: a pantoprazole-only study found serum iron 85.9 vs 83.4 ug/dL, p=0.71 [16].
• At-risk subgroups: Patients taking oral iron salts (label interaction); no rabeprazole-specific subgroup.

Regulatory status

Label section 7 lists iron salts among drugs whose absorption depends on gastric pH [1]. The label text returned lists no iron-deficiency adverse reaction; postmarketing hemolytic anemia is addressed under Oxygen delivery/utilization.

Evidence (Tier B, rabeprazole)

Case report: 59-year-old man treated with rabeprazole for GERD gradually developed iron-deficiency anemia; ferrous fumarate did not resolve it; endoscopy of the whole GI tract including the small intestine found no cause; after a switch from rabeprazole to famotidine the anemia was cured within three months [10]. Tier C class: pilot cross-sectional study, 37 PPI users (3 to 10 years; pantoprazole 18, esomeprazole 9, omeprazole 7, dexlansoprazole 2, lansoprazole 1; rabeprazole not included) vs 30 healthy controls: serum iron 16.3 vs 23.4 umol/L and hemoglobin 12.5 vs 14.3 g/dL, both p<0.001; ferritin not measured [11]. A narrative review cites the same rabeprazole case [12].

Mechanism

Acid-dependent solubility and absorption of non-heme iron (mechanism A), consistent with the label's pH-dependent absorption list [1]. Reversal on a switch to an H2 blocker in the case fits a drug-related absorption effect but is a single observation.

Counter-evidence held on record

Counter-evidence on record One case, no rechallenge, no iron indices in the abstract text retrieved [10]. The class cohort used healthy controls 18 years younger on average (57.1 vs 39.3 years) and mixed PPIs without rabeprazole [11]. Anemia and low hemoglobin are outcomes, not iron deficiency, unless iron indices are measured (Hard Rule 2). Framing caution Not a statement that rabeprazole causes iron deficiency in typical users. Unneeded iron supplementation would be the hazard for people without a confirmed deficit. No dose is recommended.

Limits on what this shows

• Null findings: A narrative review states the lower serum zinc on PPI therapy was not observed for copper [12]. In the zinc experiment, serum copper changed little with zinc supplementation in controls; no PPI-versus-control copper comparison was reported [8]. A PubMed listing combining rabeprazole with copper, zinc and vitamin D terms returned no rabeprazole copper study.
• At-risk subgroups: None identified.

Regulatory status

No copper statement in the label text returned [1].

Population evidence

Tier C class extrapolation (rabeprazole not in the cohort): pilot cross-sectional study, 37 PPI users for 3 to 10 years (pantoprazole 18, esomeprazole 9, omeprazole 7, dexlansoprazole 2, lansoprazole 1) vs 30 healthy controls: copper 1.14 +/- 0.25 vs 0.97 +/- 0.22 mg/L, p<0.001, higher in PPI users [11].

Mechanism

None named. Acid-dependent copper absorption is not established in any source opened.

Counter-evidence held on record

Counter-evidence on record One small cross-sectional pilot with healthy controls 18 years younger on average, mixed PPIs and no replication; a single comparison cannot show that the drug caused the difference. Copper is kept independent of Iron and Zinc although [11] supplies all three values (see Overlap map). Framing caution A reverse-direction, unreplicated observation in a cohort without rabeprazole. Copper supplementation would be the hazard, not the remedy; none is recommended.

Limits on what this shows

• Null findings: Total fecal organic acid concentration and blood bacteria detection did not change in [21].
• At-risk subgroups: Not defined for rabeprazole; the mouse data are in stress and NSAID-injury contexts [22][23].

Regulatory status

Not addressed as a microbiome effect in the label text returned [1].

Population evidence

Rabeprazole in the cohort, not stratified: 20 reflux-esophagitis patients received 8 weeks of esomeprazole 20 mg, rabeprazole 10 mg or lansoprazole 30 mg daily; stool Lactobacillus species rose at 4 and 8 weeks (P=0.011, P=0.002) and Streptococcus species rose (P<0.01, P<0.001); total organic acids unchanged; bacteria detected in blood 22% before and 28% after (not significant); per-PPI numbers not reported and esomeprazole was predominantly prescribed [21]. Rabeprazole listed among six PPIs: three Dutch cohorts, 1,815 participants, 211 PPI users (11.6%): lower Shannon diversity and richness, about 20% of taxa changed, oral bacteria (Rothia) and Escherichia coli increased; per-PPI counts not reported [20]. Tier B, rabeprazole: C57BL/6J mice under water-avoidance stress given rabeprazole 40 mg/kg had higher intestinal permeability and altered fecal microbiota, and transfer of that microbiota reproduced the permeability change [22]; in mice given indomethacin, rabeprazole increased operational taxonomic units and, like vonoprazan, reduced Lactobacillus johnsonii; transplanting treated-mouse contents increased injury and L. johnsonii supplementation prevented it [23].

Mechanism

Raised gastric pH allowing oral and upper-tract organisms to reach the lower gut and reduced acid-sensitive taxa (mechanism G, proposed in [20][23]); consequences for endogenous nutrient synthesis were not measured.

Counter-evidence held on record

Counter-evidence on record [21] is a single-arm 20-patient pre-post study with three PPIs and no rabeprazole count; [20] is cross-sectional with confounding by indication (its cohorts included IBD and IBS patients). The two mouse studies come from overlapping author groups and used doses that are not human-equivalent [22][23]. The human microbiome result cannot be separated by drug. Framing caution A composition finding, not a nutrient deficiency and not a statement of health harm from rabeprazole specifically. No probiotic is recommended here.

Limits on what this shows

• Null findings: No hemoglobin, hematocrit, arterial oxygenation or tissue oxygen data were located in any rabeprazole cohort.
• At-risk subgroups: Not defined.

Regulatory status

Eisai label section 6.2, postmarketing blood and lymphatic disorders: agranulocytosis, hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia [1]. These are idiosyncratic adverse reactions; frequency is not stated in the text returned.

Evidence (Tier B, rabeprazole)

Case report: 82-year-old woman developed progressive cyanosis with elevated methemoglobin during rabeprazole therapy; levels fell after discontinuation and rose on reintroduction; other medications and congenital causes were excluded; the authors state causality cannot be established from a single case and note no prior PPI cases were documented [28]. Iron route: one rabeprazole case of iron-deficiency anemia [10] (see Iron). Tier C class: hemoglobin 12.5 vs 14.3 g/dL in a PPI cohort that excluded rabeprazole [11].

Mechanism

For methemoglobinemia, hemoglobin oxidation, as framed by the case authors; how rabeprazole would cause it is not established [28]. For anemia through iron, see Iron. Mechanism otherwise absent.

Counter-evidence held on record

Counter-evidence on record A single suspected-causality case read as an abstract through OpenAlex and a summarizing tool; the methemoglobin percentages were not captured [28]. Anemia and low hemoglobin are outcomes, not nutrient deficiencies (Hard Rule 2). Kept independent from ATP production (Hard Rule 7); it shares the iron case and the class cohort with the Iron entry (see Overlap map). Framing caution Not a claim that rabeprazole impairs oxygen delivery in typical users. No iron or antioxidant supplement is recommended, and no dose is given.

Limits on what this shows

• Why no grade: The dual condition in Step 7 is met. (1) No Tier B or Tier C evidence supports even a yellow grade: the only PubMed item returned for rabeprazole with ATP, energy metabolism or oxidative phosphorylation terms describes inactivation of a glycolytic enzyme (triosephosphate isomerase) of a parasitic microsporidium in vitro and tested no human enzyme or cell [32]; the class mitochondrial datum [27] concerns mitophagy in vascular smooth muscle, is graded under Mitochondrial burden and does not measure ATP. (2) None of the six consumer or reference pages opened made an energy, fatigue-as-ATP or mitochondrial claim about rabeprazole; fatigue and weakness appear only as symptoms of low magnesium on a side-effect page [35], which is covered by the Magnesium entry. This is a disclosed gap, not a finding of safety.

Channels tried and outcome

PubMed HTML listing pages through the fetch tool (worked): "rabeprazole ATP OR energy metabolism OR oxidative phosphorylation" returned one unrelated parasite-enzyme item [32]; "rabeprazole mitochondria OR mitochondrial" returned the same single item; "proton pump inhibitor mitochondrial dysfunction" returned 14 results, none measuring ATP in rabeprazole-exposed tissue (two PPI-specific hits were read at abstract level: one names omeprazole, esomeprazole and lansoprazole [27], the other esomeprazole). DailyMed labels (worked via fetch tool): read for relevant sections; no energy or ATP effect described [1][2]. OpenAlex single-record lookups (worked, used for abstracts); OpenAlex and Crossref search endpoints returned 429. Web search: budget exhausted (200 of 200) before any ATP-specific query could be run. Europe PMC and Semantic Scholar were not tried in this review (direct access is blocked by organization policy and the fetch tool was spent on PubMed, OpenAlex and publisher pages).

Gap type

Genuine absence on the PubMed channel across three phrasings, but search breadth was limited by tooling: web search, OpenAlex search, Crossref search, Europe PMC and Semantic Scholar were unavailable or untried. A later revision should re-check this category with those channels.

Counter-evidence held on record

Counter-evidence on record Not applicable; no data to counter. Kept independent from Oxygen delivery/utilization and Mitochondrial burden as required. Framing caution Do not read this entry as reassurance. It states only that no evidence was found in the channels that could be searched.