title: Pharmacokinetic and pharmacodynamic interaction between allopurinol and probenecid in healthy subjects.
abstract: OBJECTIVE
  Combination therapy with allopurinol and probenecid is used to treat tophaceous 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 mmol/L) and combination therapy (0.09+/-0.02 mmol/L) compared with baseline (0.30+/-0.05 mmol/L).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Faculty of Pharmacy, University of Sydney, Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Sydney, New South Wales, Australia.
authors.forename: Sophie L
authors.initials: SL
authors.lastname: Stocker
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Williams
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McLachlan
authors.forename: Garry G
authors.initials: GG
authors.lastname: Graham
authors.forename: Richard O
authors.initials: RO
authors.lastname: Day
mesh_terms: D000328:Adult; D000493:Allopurinol / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D000704:Analysis of Variance; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D003404:Creatinine / Q000652:urine; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D010117:Oxypurinol / Q000097:blood / Q000378:metabolism; D011339:Probenecid / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D013997:Time Factors; D014527:Uric Acid / Q000097:blood / Q000652:urine
chemical_list: D014527:Uric Acid; D000493:Allopurinol; D003404:Creatinine; D010117:Oxypurinol; D011339:Probenecid