probenecid
uricosuric agent· Brands: Benemid, Proben, ProbalanPO
Mechanism of action
Probenecid is a uricosuric agent that blocks the reabsorption of uric acid in the proximal tubules of the kidney, thereby increasing urinary excretion of urate. It also competitively inhibits the tubular secretion of organic acids, including penicillins and other drugs, so it is used to prolong and increase their plasma concentrations.
Pharmacokinetics
Probenecid is rapidly and completely absorbed from the gastrointestinal tract. It is extensively bound to plasma albumin (about 85%) and is metabolised in the liver to inactive metabolites. The elimination half-life is dose dependent and ranges from 4 to 12 hours. It is excreted in urine, both as unchanged drug and as metabolites.
Indications & dosing
Gout and hyperuricemia
Initial dose; may be increased as needed. Monitor serum uric acid.
- adult · PO: 250 mg twice daily · Initial dose; may be increased as needed. Monitor serum uric acid.
Adjunct to penicillin therapy
Inhibits renal tubular secretion of penicillins, increasing their plasma concentrations.
- adult · PO: 500 mg four times daily · Inhibits renal tubular secretion of penicillins, increasing their plasma concentrations.
Contraindications & precautions
- Hypersensitivity to probenecid · Patients with a history of anaphylaxis or severe allergic reaction to probenecid should not receive the drug.
- Blood dyscrasias · Probenecid is contraindicated in patients with a history of blood dyscrasias such as aplastic anaemia or haemolytic anaemia.
- Uric acid renal stones · Probenecid increases urinary uric acid concentration and may precipitate uric acid stones in predisposed patients.
- Concurrent salicylate therapy · Salicylates antagonise the uricosuric effect of probenecid, so concurrent use should be avoided.
- Ensure adequate hydration and alkali intake to prevent uric acid stone formation.
- Avoid concurrent salicylates as they antagonise the uricosuric effect.
- Use with caution in renal impairment; dosage adjustment may be needed.
- Monitor for increased toxicity of co-administered drugs that undergo renal tubular secretion (e.g., penicillins, NSAIDs, methotrexate).
- Caution in patients with a history of peptic ulcer disease as probenecid may exacerbate gastrointestinal symptoms.
Adverse effects
- Nausea and vomiting
- Dizziness
- Headache
- Rash
- Anaphylaxisserious
- Blood dyscrasias (e.g., aplastic anaemia, haemolytic anaemia)serious
- Nephrotic syndromeserious
- Hepatic necrosisserious
Interactions
- methotrexatemajorAvoid co-prescription. If treatment with both drugs is essential, do not use high-dose methotrexate. For low-dose methotrexate, consider a substantial dose reduction, or alternative uricosuric or anti-inflammatory agents. Monitor plasma methotrexate concentrations, full blood count, serum creatinine, and liver function tests frequently. Provide supportive care such as hydration and leucovorin rescue as appropriate.
Renal & hepatic adjustment
- eGFR 0–29: Avoid. Probenecid is ineffective and the risk of urate stones is increased. (avoid)
- eGFR 30–60: Use with caution. May be effective but monitor renal function and serum uric acid.
- eGFR 61+: No adjustment required.
Monitoring, pregnancy & toxicity
- Serum uric acid · At baseline and periodically during treatment
- Renal function (serum creatinine, eGFR) · At baseline and periodically
- Hydration and urine output · During therapy
- Signs of toxicity from co-administered drugs · Throughout therapy, especially when starting or increasing the dose
- Hypersensitivity reactions (rash, fever) · During therapy
- Pregnancy: Probenecid is not recommended during pregnancy unless clearly necessary. Limited human data; animal studies have not shown teratogenic effects. If use is proposed, weigh the benefits against potential risks and consult a specialist.
- Toxicity: Gastrointestinal symptoms (nausea, vomiting, abdominal pain) · Supportive care, ensure hydration, monitor electrolytes.
- Toxicity: Central nervous system effects (confusion, seizures) · Supportive care, control seizures with benzodiazepines, monitor vital signs.
- Toxicity: Renal toxicity (acute kidney injury) · Maintain hydration, monitor renal function, consider haemodialysis if severe.
Clinical notes
Probenecid is used to reduce uric acid concentration in chronic gout and to increase the concentration of certain antibacterial drugs, such as penicillins, when high levels are required. It should be taken with food or milk to reduce gastrointestinal upset. Adequate fluid intake should be maintained to prevent urate stones. It is contraindicated in renal failure and in patients with a history of uric acid stones. Probenecid may affect the action of other drugs by inhibiting their renal excretion, so careful monitoring is required.
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BNF; local formulary