title: The population pharmacokinetics of allopurinol and oxypurinol in patients with gout.
abstract: OBJECTIVE
  The aims of this study were to develop a population pharmacokinetic model for allopurinol and oxypurinol and to explore the influence of patient characteristics on allopurinol and oxypurinol pharmacokinetics.
  
  
  METHODS
  Data from 92 patients with gout and 12 healthy volunteers were available for analysis. A parent-metabolite model with a two-compartment model for allopurinol and a one-compartment model for oxypurinol was fitted to the data using non-linear mixed effects modelling.
  
  
  RESULTS
  Renal function, fat-free mass (FFM) and diuretic use were found to predict differences in the pharmacokinetics of oxypurinol. The population estimates for allopurinol clearance, inter-compartmental clearance, central and peripheral volume were 50, 142 L/h/70 kg FFM, 11.4, 91 L/70 kg FFM, respectively, with a between-subject variability of 33 % (coefficient of variance, CV) for allopurinol clearance. Oxypurinol clearance and volume of distribution were estimated to be 0.78 L/h per 6 L/h creatinine clearance/70 kg FFM and 41 L/70 kg FFM in the final model, with a between-subject variability of 28 and 15 % (CV), respectively.
  
  
  CONCLUSIONS
  The pharmacokinetic model provides a means of predicting the allopurinol dose required to achieve target oxypurinol plasma concentrations for patients with different magnitudes of renal function, different body mass and with or without concomitant diuretic use. The model provides a basis for the rational dosing of allopurinol in clinical practice.
authors.affiliation: School of Pharmacy, University of Otago, PO Box 56, Dunedin, New Zealand. dan.wright@otago.ac.nz
authors.forename: Daniel F B
authors.initials: DF
authors.lastname: Wright
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Stamp
authors.forename: Tony R
authors.initials: TR
authors.lastname: Merriman
authors.forename: Murray L
authors.initials: ML
authors.lastname: Barclay
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Duffull
authors.forename: Nicholas H G
authors.initials: NH
authors.lastname: Holford
mesh_terms: D000493:Allopurinol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001823:Body Composition; D015331:Cohort Studies; D004232:Diuretics / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006073:Gout / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D006074:Gout Suppressants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008954:Models, Biological; D010117:Oxypurinol / Q000097:blood / Q000493:pharmacokinetics*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
chemical_list: D004232:Diuretics; D004791:Enzyme Inhibitors; D006074:Gout Suppressants; D000493:Allopurinol; D014969:Xanthine Oxidase; D010117:Oxypurinol