Pharmacokinetic and pharmacodynamic interaction between allopurinol and probenecid in healthy subjects

Background and objective: Combination therapy with allopurinol and probenecid is used to treat tophaccous gout in patients who do not respond sufficiently to allopurinol alone. However, the potential interaction between these drugs has not been systematically investigated. The objective of this study was to investigate the pharmacokinetics and hypouricaemic effect of oxypurinol (the active metabolite of allopurinol) and probenecid when administered alone and in combination in healthy subjects. Methods: An open-label, randomized, three-way crossover clinical trial was conducted in 12 healthy adults. Subjects were randomized to receive treatment for 7 days with allopurinol (150 mg twice daily), probenecid (500 mg twice daily) or combination therapy with both drugs, with a 7-day washout period between treatments. Venous blood samples were collected predose (at 0 hours) and 1, 2, 3, 4, 6, 8, 10 and 12 hours after dosage for determination of oxypurinol and/or probenecid concentrations. Plasma and urinary urate concentrations were determined on each study day and at the end of each washout period. Pharmacokinetic and pharmacodynamic parameters were analysed using two-way ANOVA. Results: Coadministration of allopurinol and probenecid significantly reduced average steady-state plasma oxypurinol concentrations (mean +/- SD: allopurinol alone 9.7 +/- 2.1 mg/L vs combination 5.1 +/- 1.0 mg/L, p < 0.001). Probenecid concentrations were unaffected. Plasma urate concentrations decreased (p < 0.01) during allopurinol therapy (0.16 +/- 0.05 mmol/L), probenecid therapy (0.13 +/- 0.02 nunol/L) and combination therapy (0.09 +/- 0.02 mmol/L) compared with baseline (0.30 +/- 0.05 mmol/L). Conclusion: Coadministration of allopurinol and probenecid to healthy subjects had a greater hypouricaemic effect than either allopurinol or probenecid alone, despite a reduction in plasma oxypurinol concentrations when the drugs were taken concomitantly.