Pharmacodynamics of oxypurinol after administration of allopurinol to healthy subjects

1 Eight healthy subjects received 50, 100, 300, 600 and 900 mg allopurinol daily for 1 week each, in random order with 1 week separating each treatment period. The pre-dose plasma concentration of oxypurinol, the extent of inhibition of xanthine oxidase, plasma urate concentration and urine urate excretion rate were assessed on the last 2 days of each treatment week. 2 The ratio of 1-methyluric acid (1MU) over l-methylxanthine (1MX) in the urine, following a dose of 50 mg 1MX infused intravenously over 20 min, was used to measure the inhibition of xanthine oxidase. 3 The steady-state plasma concentration of oxypurinol increased linearly with increasing dose of allopurinol between 50 mg to 600 mg day(-1), with a weak indication of saturation at the higher 900 mg day(-1) dose rate, 4 The relationships between plasma oxypurinol concentration and xanthine oxidase inhibition (1MU/1MX ratio), plasma urate concentration and urine urate excretion rate were fitted to an inhibition sigmoid E(max) model and the C-50 values for oxypurinol were 26.38+/-4.87, (mean+/-s.d.) 36.58+/-8.36 and 24.61+/-9.08 mu M, respectively. 5 1MU/1MX ratio appeared to be a reliable index of xanthine oxidase activity in vivo as the C-50 for oxypurinol observed for 1MU/1MX ratio, plasma urate concentration and urine urate excretion rate were similar. 6 The concentration of oxypurinol required for inhibition of xanthine oxidase, as indicated by C-50 was lower than those often observed in clinical practice.