PROBENECID W/ COLCHICINE
Clinical safety rating
safeIncreases levels of many drugs by inhibiting their renal secretion (eg penicillins methotrexate) Can cause GI upset and nephrotic syndrome.
Probenecid inhibits renal tubular reabsorption of uric acid, increasing its excretion. Colchicine binds to tubulin, inhibiting microtubule polymerization and reducing inflammatory cell chemotaxis.
| Metabolism | Probenecid: Hepatic via glucuronidation, oxidation; inhibits renal tubular secretion of many drugs. Colchicine: Hepatic via CYP3A4 and P-glycoprotein (P-gp); undergoes enterohepatic recirculation. |
| Excretion | Probenecid: Renal (70-80% as unchanged drug and metabolites, primarily via tubular secretion); Colchicine: Hepatic metabolism (approx. 80%) and renal excretion (10-20% unchanged). Fecal excretion of metabolites accounts for a minor fraction. |
| Half-life | Probenecid: 5-8 hours (terminal half-life, prolonged in renal impairment); Colchicine: 26-31 hours (mean terminal half-life in adults, can be extended in elderly or renal/hepatic impairment). |
| Protein binding | Probenecid: 85-95% bound to plasma albumin; Colchicine: 39-44% bound to albumin and alpha1-acid glycoprotein. |
| Volume of Distribution | Probenecid: 0.15-0.2 L/kg (highly confined to plasma and extracellular fluid); Colchicine: 2-5 L/kg (extensive tissue distribution, particularly in leukocytes and liver). |
| Bioavailability | Probenecid: Oral bioavailability approximately 100% (well absorbed, but first-pass metabolism reduces systemic exposure to parent drug); Colchicine: Oral bioavailability 24-45% (subject to first-pass metabolism and transport by P-glycoprotein). |
| Onset of Action | Probenecid: Oral, 30-60 minutes (peak effect on uric acid excretion at 2-4 hours); Colchicine: Oral, 12-24 hours for gout flare relief (peak anti-inflammatory effect at 24-48 hours). |
| Duration of Action | Probenecid: Uricosuric effect persists for 8-12 hours after a single dose; Colchicine: Anti-inflammatory effect lasts 48-72 hours after a single oral dose, but clinical improvement may take 1-2 days. |
| Molecular Weight | Probenecid: 285.36 Da; Colchicine: 399.44 Da |
1 tablet (500 mg probenecid / 0.5 mg colchicine) orally twice daily, with or without food.
| Dosage form | TABLET |
| Renal impairment | Contraindicated if GFR < 30 mL/min; for GFR 30-50 mL/min, reduce dose to 1 tablet once daily; for GFR > 50 mL/min, no adjustment needed. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce colchicine dose by 50% (use combination product cautiously); Child-Pugh C: contraindicated due to colchicine toxicity risk. |
| Pediatric use | Not recommended for pediatric use; safety and efficacy not established. |
| Geriatric use | Start with 1 tablet once daily; monitor renal function and colchicine toxicity due to age-related decline in GFR and increased sensitivity. |
| 1st trimester | Contraindicated due to teratogenic potential; colchicine may cause chromosomal abnormalities and probenecid may interfere with fetal development. |
| 2nd trimester | Avoid use; risk of fetal harm outweighs benefits. Colchicine associated with fetal toxicity. |
| 3rd trimester | Avoid use; probenecid may cause hemolytic anemia in newborns with G6PD deficiency; colchicine may cause neonatal toxicity. |
Clinical note
Increases levels of many drugs by inhibiting their renal secretion (eg penicillins methotrexate) Can cause GI upset and nephrotic syndrome.
| FDA category | Animal |
| Placental transfer | Both drugs cross the placenta. Probenecid: moderate transfer; colchicine: high transfer, accumulates in fetal tissues. |
| Breastfeeding | Both drugs are excreted into breast milk. Colchicine may cause diarrhea in infants; probenecid can cause rash. Avoid use in breastfeeding women due to potential for serious adverse effects in infants. Consider alternative therapy. |
| Lactation Rating | L4 - Hazardous |
| Teratogenic Risk | Risk cannot be ruled out. Colchicine is associated with chromosomal abnormalities and fetal harm at high doses in animal studies; human data limited. Probenecid not teratogenic in animals. First trimester: avoid unless benefit outweighs risk. Second/third trimester: use only if clearly needed. |
| Fetal Monitoring | Monitor CBC, renal function, liver enzymes; colchicine: monitor for neuromuscular toxicity, diarrhea, vomiting. Fetal: ultrasound for growth and anatomy if exposed in first trimester. |
| Fertility Effects | Colchicine may impair spermatogenesis (reversible); probenecid not known to affect fertility. |
■ FDA Black Box Warning
Colchicine can cause fatal toxicity if not dosed correctly; fatalities have occurred with doses as low as 0.8 mg in patients with renal or hepatic impairment, or in combination with P-glycoprotein or CYP3A4 inhibitors.
| Common Effects | Hyperuricemia |
| Serious Effects |
History of hypersensitivity to probenecid or colchicineSevere renal impairment (CrCl < 30 mL/min)Severe hepatic impairmentActive peptic ulcer diseaseConcomitant use with P-glycoprotein or CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole) due to increased colchicine toxicityBlood dyscrasias or bone marrow suppressionGouty arthritis during acute attack (probenecid may exacerbate)
| Precautions | Blood dyscrasias (aplastic anemia, agranulocytosis), hepatotoxicity, neuromuscular toxicity, renal impairment, drug interactions with P-gp and CYP3A4 inhibitors, use with caution in elderly and debilitated patients. |
| Food/Dietary | Avoid high-purine foods (organ meats, shellfish, red meat, beer) as they increase uric acid and reduce drug efficacy. Alcohol, especially beer, contraindicated. Acidic foods (cranberries, citrus) may increase colchicine absorption; limit large amounts. Grapefruit may increase colchicine levels; avoid. |
| Clinical Pearls | Probenecid reduces renal excretion of colchicine, increasing colchicine toxicity risk; dose adjustment required. Contraindicated in G6PD deficiency and blood dyscrasias. Monitor CBC and renal function. Use with caution in patients with peptic ulcer disease (probenecid may exacerbate). Colchicine neuromyopathy risk increases with concurrent statins or cyclosporine. |
| Patient Advice | Take with food or milk to reduce GI upset. · Drink plenty of fluids (2-3 L/day) to prevent kidney stones and help urate excretion. · Avoid alcohol, as it can increase uric acid levels and precipitate gout attacks. · Stop at first signs of infection, sore throat, or easy bruising (myelosuppression). · Report muscle pain or weakness (colchicine myopathy), especially if on statins. · Do not exceed prescribed dose; colchicine overdose can be fatal. · May cause gout flares initially; continue medication and contact provider if flares persist. |
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