Citric Acid
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Citric Acid: From Pharmaceutical Excipient to Stomach Disease
One-Sentence Summary
Citric acid (DrugBank DB04272) is a naturally occurring organic acid present in gastric juice and a central intermediate of the Krebs (TCA) cycle, widely used as a pharmaceutical excipient, food additive, and diagnostic adjunct in the ¹³C-urea breath test for Helicobacter pylori detection, but it carries no formally registered therapeutic indication in Australia. The TxGNN model predicts it may have relevance to Stomach Disease (prediction score 99.74%), with 29 registered clinical trials identified — none of which directly test citric acid as a therapeutic intervention for stomach disease — and 20 publications, predominantly basic science and observational metabolomics studies, currently supporting this direction. Overall evidence strength is L4 (preclinical/mechanistic), and this candidate is currently classified as a Research Question rather than an actionable repurposing lead.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | No registered therapeutic indication; used as pharmaceutical excipient, food additive, and diagnostic adjunct |
| Predicted New Indication | Stomach Disease |
| TxGNN Prediction Score | 99.74% |
| Evidence Level | L4 |
| Australia Market Status | Not marketed |
| Number of ARTG Entries | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available for citric acid in this submission. Based on published scientific literature, citric acid is a naturally occurring tricarboxylic weak acid that serves as a central intermediate in the mitochondrial Krebs (TCA) cycle — the primary energy metabolism pathway of virtually all aerobic cells. Critically, it is also a quantifiable normal constituent of human gastric juice (PMID 6027230), which likely underpins the TxGNN model’s high-scoring association with stomach disease.
The most clinically established link between citric acid and the stomach is its role as a diagnostic adjunct: a citric acid test meal is administered prior to the ¹³C-urea breath test to delay gastric emptying, improving test accuracy for H. pylori detection in Asian populations (PMID 31505905). There is also preclinical evidence that MX1 — a compound combining the H₂-receptor antagonist roxatidine’s active metabolite with a bismuth–citric acid complex — exhibits gastroprotective activity against restraint stress ulcers in rats (PMID 9379358), suggesting that citric acid’s metal-chelating properties may contribute to mucosal protection in combination formulations.
From a metabolomics perspective, altered citric acid levels and broader TCA cycle dysregulation have been consistently identified in gastric cancer patients and H. pylori-infected stomach tissue compared to healthy controls (PMID 38959111, PMID 35900644, PMID 28546118). While this establishes an associative biological relationship, it reflects a biomarker signal rather than a direct therapeutic mechanism. No clinical interventional data currently supports citric acid as a standalone treatment for any stomach disease.
Clinical Trial Evidence
Twenty-nine registered trials were identified in the evidence search; however, none directly test citric acid as a therapeutic intervention for stomach disease. All trials received a relevance grade of C (indirect or unrelated). The ten most disease-contextually relevant trials are listed below for completeness.
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT03812380 | Phase 3 | Terminated | 62 | Effervescent calcium magnesium citrate to prevent PPI-associated complications (fractures, hypomagnesaemia, CKD) in patients on long-term gastric acid suppression — citrate is the active salt; trial terminated early |
| NCT03320538 | N/A | Completed | 360 | Multicenter RCT of traditional Chinese herbal medicine (Hou Gu Mi Xi) vs placebo for peptic ulcer disease with spleen qi deficiency — disease-relevant (stomach), no citric acid component |
| NCT07122284 | N/A | Completed | 42 | Metagenomic and metabolomic characterisation of gut microbiota in concurrent H. pylori infection and SIBO — stomach disease context, observational design, no citric acid intervention |
| NCT03425747 | Phase 4 | Completed | 26 | Calcium citrate vs calcium carbonate for management of chronic hypoparathyroidism — directly compares the citrate salt form but not for stomach disease |
| NCT05753306 | Phase 2 | Recruiting | 40 | Robotic cytoreduction and HIPEC for gastric cancer with limited peritoneal metastasis — disease-relevant (gastric cancer), no citric acid |
| NCT05196945 | Phase 4 | Unknown | 316 | Vonoprazan + amoxicillin dual therapy vs standard quadruple therapy for first-line H. pylori eradication — disease-relevant (gastric), no citric acid |
| NCT06760065 | Phase 3 | Not yet recruiting | 316 | Keverprazan + amoxicillin vs susceptibility-guided quadruple therapy for rescue H. pylori eradication — disease-relevant (gastric), no citric acid |
| NCT03342456 | Phase 4 | Completed | 184 | Ilaprazole/doxycycline bismuth quadruple therapy for H. pylori-associated duodenal ulcer — disease-relevant, no citric acid |
| NCT04350346 | N/A | Unknown | 70 | Motilitone vs Gasmotin for symptom relief in gallstone patients with functional dyspepsia — stomach disease context, no citric acid |
| NCT02830789 | N/A | Completed | 38 | Calcium citrate vs calcium carbonate for secondary hyperparathyroidism following Roux-en-Y gastric bypass — post-gastric surgery context, citrate salt used |
No trials were identified in the ANZCTR (Australian New Zealand Clinical Trials Registry) or WHO ICTRP for this drug–disease combination.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 31505905 | 2019 | Observational/Diagnostic Validation | Gut and Liver | Citric acid test meal improves accuracy of the ¹³C-urea breath test for H. pylori in Asian populations by delaying gastric emptying — the most directly relevant clinical application of citric acid in stomach disease |
| 9379358 | 1997 | Basic Science (Animal) | J Pharmacy and Pharmacology | MX1 (roxatidine active metabolite + bismuth–citric acid complex) demonstrates gastroprotective activity against restraint stress ulcers in rats — citric acid as a functional component of a gastroprotective compound |
| 6027230 | 1967 | Basic Science | Gastroenterology | Quantification of lactic, pyruvic, citric, and uric acid in normal human gastric juice — establishes citric acid as a natural constituent of the gastric environment |
| 35900644 | 2022 | Observational/Biomarker | Metabolomics | Elevated serum L-carnitine and citric acid levels, negatively correlated with alkaline phosphatase, are detectable in Korean patients before gastric cancer onset — positions TCA metabolites as potential early-detection biomarkers |
| 38959111 | 2024 | Cohort/Transcriptomic | Cell Reports | TCA cycle upregulation characterises the better-prognosis MSC1 molecular subtype of gastric cancer — implicates citric acid metabolism in gastric tumour biology and potential therapeutic targeting |
| 28546118 | 2017 | Basic Science (Animal) | Microbial Pathogenesis | Metabolomic analysis of H. pylori SS1-infected mouse stomach tissue reveals progressive TCA cycle disruption (including citrate pathway) at 1, 3, and 6 months post-infection |
| 26088916 | 2015 | Observational/Metabolomics | Applied Biochemistry and Biotechnology | LC/MS metabolomics identifies TCA cycle pathway disruption, including altered citric acid, as a potential diagnostic and prognostic biomarker in gastric cancer — exploratory |
| 9604442 | 1998 | Review | British Medical Bulletin | Overview of non-invasive ¹³C/¹⁴C-urea breath tests for active H. pylori infection; discusses citric acid as a standard test meal component and its role in optimising test performance |
| 2072799 | 1991 | Review | Medical Clinics of North America | Diet and nutrition in peptic ulcer disease; notes that acidic foods including citric acid sources may directly irritate the gastric mucosa — relevant to acid–mucosal microenvironment interaction |
| 37477784 | 2024 | Review | Clinical and Translational Oncology | Energy metabolism including the TCA/citric acid cycle axis as an emerging therapeutic target in gastric cancer — provides theoretical framework for further repurposing exploration |
Australia Market Information
Citric acid (DrugBank DB04272) has no registered products on the Australian Register of Therapeutic Goods (ARTG). It is currently not marketed as a therapeutic agent in Australia.
Citric acid is present as an excipient or pH-adjusting agent in many TGA-listed and registered products, but these entries do not constitute a therapeutic indication for citric acid itself. Any future therapeutic application would require a new ARTG registration or a clinical trial notification (CTN) process.
Safety Considerations
Please refer to the TGA-approved Product Information (PI) for safety information once a relevant product is registered. No drug–drug interaction data, key warnings, or formal contraindications specific to citric acid as a therapeutic agent were identified in this evidence pack.
Practical note for prescribers: At concentrations used as food additives and pharmaceutical excipients, citric acid is generally recognised as safe. At higher therapeutic concentrations, considerations include potential mucosal irritation (particularly gastric and oesophageal), dental enamel erosion with prolonged oral exposure, and — for preparations containing citrate salts — the risk of metabolic alkalosis in patients with impaired renal function. These considerations should be formally characterised in any dose-finding study.
Conclusion and Next Steps
Decision: Hold
Rationale: The TxGNN model’s high prediction score (99.74%) for citric acid in stomach disease is biologically plausible given its status as a natural gastric juice component and TCA cycle intermediate; however, this prediction reflects a mechanistic and metabolomic association rather than a therapeutic one — all 29 identified clinical trials are unrelated to citric acid treatment of stomach disease, and the 20 literature items are exclusively preclinical, basic science, or observational in design (Evidence Level L4). The existing clinical evidence positions citric acid as a diagnostic adjunct (¹³C-UBT test meal), not a therapeutic agent.
To proceed to a Research Question stage, the following is needed:
- MOA and pharmacology data: Retrieve the full DrugBank DB04272 entry including pharmacokinetics, bioavailability, and safety profile relevant to therapeutic dosing
- Indication sub-type definition: Specify the target stomach disease (e.g., H. pylori gastritis, peptic ulcer, functional dyspepsia, or gastric cancer metabolic reprogramming) — each requires a distinct mechanistic rationale and study design
- Proof-of-concept study design: A pilot clinical study evaluating citric acid as an adjunct in H. pylori eradication regimens or as a mucosal microenvironment modifier provides the most mechanistically grounded starting point, given the ¹³C-UBT application
- Formulation and dose-ranging: Establish clinically tolerable citric acid concentrations and delivery formats (e.g., buffered oral solution, effervescent tablet) prior to any interventional study, as mucosal irritation at elevated concentrations is a recognised concern
- ARTG pathway planning: As no therapeutic product containing citric acid as an active ingredient is registered in Australia, engagement with the TGA regarding the regulatory pathway (new registration or CTN) would be required before any local clinical trial proceeds
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.