PROBENECID W/ COLCHICINE
Clinical safety rating: safe
Increases 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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
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 |
| Breastfeeding | Colchicine: limited excretion into breast milk; M/P ratio ~0.4; low relative infant dose (~5% maternal weight-adjusted dose). Probenecid: excreted in milk but no adverse reports. Consider alternative if infant <3 months or G6PD deficiency. |
| 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. |
■ 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 |
Hypersensitivity to probenecid or colchicine, concurrent use of P-gp or strong CYP3A4 inhibitors (e.g., clarithromycin, cyclosporine, ketoconazole), severe renal impairment (CrCl <30 mL/min), severe hepatic impairment, pre-existing blood dyscrasias.
| 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. |
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| 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. |