Probenecid
| Evidence Level: L4 | Predicted Indications: 3 |
Table of Contents
Probenecid: From Gout to Renal Hypouricemia
One-Sentence Summary
Probenecid is a uricosuric drug, originally used to treat gout and hyperuricemia. The TxGNN model predicts it may be effective for renal hypouricemia, but there are 0 clinical trials and 20 publications in the data compiled for this report. These publications only describe the disease or use probenecid as a diagnostic probe; none supports therapeutic use.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Gout; hyperuricemia (per knowledge-graph indication data; no label text available) |
| Predicted New Indication | Renal hypouricemia |
| TxGNN Prediction Score | 99.73% |
| Evidence Level | L4 |
| US Market Status | Cancelled only (no currently valid licenses) |
| Number of NDAs | 7 (all cancelled; 1 NDA and 6 ANDAs) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data is not available in the data compiled for this report. Based on known pharmacology, probenecid inhibits the renal urate transporter URAT1 (SLC22A12) and the organic anion transporters OAT1/OAT3. This blocks urate reabsorption in the proximal tubule and increases uric acid excretion, which is why it lowers serum urate in gout.
The prediction is therefore mechanistically doubtful. Renal hypouricemia is mainly caused by loss-of-function mutations in URAT1 (SLC22A12), or in some cases GLUT9, which already produce excessive urinary urate excretion and low serum urate. A drug that further increases urate excretion would be expected to worsen the condition, not treat it. The high score (0.997) most likely reflects the drug’s close network association with urate transport, not a therapeutic benefit.
In the literature, probenecid appears only as a pharmacological probe. Several case reports use the response of uric acid clearance to probenecid and pyrazinamide to classify the type of tubular defect.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
The compiled literature consists of reviews, case reports and genetic or mechanistic studies. There are no RCTs, and none evaluates probenecid as a treatment.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 16678460 | 2006 | Review | Molecular Genetics and Metabolism | Hereditary renal hypouricemia is mostly caused by loss-of-function SLC22A12 (URAT1) mutations |
| 31650389 | 2020 | Review | Clinical Rheumatology | Narrative review of hypouricemia causes, aimed at rheumatologists |
| 14694169 | 2004 | Cohort/Genetic study | J Am Soc Nephrol | SLC22A12 sequencing in 32 Japanese patients; links URAT1 variants to urate excretion |
| 7771493 | 1995 | Review/Case report | Am J Kidney Dis | Exercise-induced acute renal failure in renal hypouricemia; focus on prevention |
| 854144 | 1977 | Case study | Nephron | Uric acid clearance responded only weakly to probenecid and pyrazinamide, suggesting a reabsorption defect |
| 2709741 | 1989 | Case report | Klin Wochenschr | Acute renal failure from uric acid nephropathy; probenecid enhanced urate excretion (diagnostic use) |
| 8533596 | 1995 | Case report | Acta Paediatr Jpn | Child with acute renal failure after exercise; probenecid and pyrazinamide tests showed a total defect of urate reabsorption |
| 3808147 | 1987 | Case report | Nephron | Familial renal hypouricemia with clear responses to probenecid or pyrazinamide (intact reabsorption) |
| 8341392 | 1993 | Case report | Nephron | New type with no urate response to probenecid or pyrazinamide |
| 14747372 | 2004 | Mechanistic study | J Am Soc Nephrol | Mouse URAT1 homologue localization and urate transport function |
US Market Information
All seven authorizations are cancelled, and no approved-indication text is available.
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ANDA080966 | Probenecid | Tablet, film coated | Not available |
| ANDA084442 | Probenecid | Tablet, film coated | Not available |
| ANDA217020 | Probenecid | Tablet | Not available |
| NDA213972 | ORLYNVAH | Tablet, film coated | Not available |
| ANDA084279 | Probenecid and Colchicine | Tablet | Not available |
Safety Considerations
- Contraindication-related conditions (knowledge graph, not label text): The knowledge graph links probenecid to contraindication with liver failure, kidney disease and impaired renal function, hematologic disease, thrombocytopenia, peptic ulcer disease, and muscle disorders (myopathy, rhabdomyolysis). It also lists leukopenia, agranulocytosis and several congenital neutropenias, as well as diarrheal disease and Clostridium difficile colitis. These associations need confirmation against the package insert.
- Drug Interactions: 71 interactions were identified. Major interactions include:
- Phenylbutyric acid
- Glycerol phenylbutyrate
Moderate interactions include:
- Acetylsalicylic acid
- Sulfonylureas and related antidiabetics (chlorpropamide, glimepiride, glipizide, glyburide, tolbutamide, tolazamide, acetohexamide)
- Meglitinides (repaglinide, nateglinide)
- Disease-specific concern: Renal hypouricemia carries a risk of exercise-induced acute renal failure and urolithiasis. Further increasing urinary urate excretion could aggravate both.
Conclusion and Next Steps
Decision: Hold
Rationale: The prediction rests on a computational score alone. No clinical trials exist, and the literature never supports therapeutic use. The mechanism suggests probenecid would worsen a condition already marked by excessive urate excretion. All US licenses are also cancelled.
To proceed, the following is needed:
- Package insert warnings and contraindications (a blocking gap for safety screening)
- Mechanism-of-action data from DrugBank
- Mechanistic or preclinical evidence that probenecid could benefit URAT1-deficient renal hypouricemia, if any exists
- Confirmation of a clear unmet therapeutic need, since renal hypouricemia is often asymptomatic
Other predictions (both Hold, L5):
- Lesch-Nyhan syndrome (score 99.39%): There is no clinical evidence. Probenecid would not address the neurobehavioral features, and it could raise the risk of urate stones in patients who already overexcrete urate. Xanthine oxidase inhibitors are the standard of care.
- Partial HPRT deficiency (score 99.37%): There are no trials or literature. The mechanism overlaps with gout, but the risk of uric acid nephrolithiasis in overproducers makes xanthine oxidase inhibitors preferable.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.