PHARMACODYNAMICS OF OXYPURINOL AFTER ADMINISTRATION OF ALLOPURINOL TOHEALTHY-SUBJECTS

1 Eight healthy subjects received 50, 100, 300, 600 and 900 mg allopur inol daily for 1 week each, in random order with 1 week separating eac h treatment period. The pre-dose plasma concentration of oxypurinol, t he extent of inhibition of xanthine oxidase, plasma urate concentratio n and urine urate excretion rate were assessed on the last 2 days of e ach treatment week. 2 The ratio of 1-methyluric acid (1MU) over l-meth ylxanthine (1MX) in the urine, following a dose of 50 mg 1MX infused i ntravenously over 20 min, was used to measure the inhibition of xanthi ne oxidase. 3 The steady-state plasma concentration of oxypurinol incr eased linearly with increasing dose of allopurinol between 50 mg to 60 0 mg day(-1), with a weak indication of saturation at the higher 900 m g day(-1) dose rate, 4 The relationships between plasma oxypurinol con centration and xanthine oxidase inhibition (1MU/1MX ratio), plasma ura te concentration and urine urate excretion rate were fitted to an inhi bition 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, respecti vely. 5 1MU/1MX ratio appeared to be a reliable index of xanthine oxid ase activity in vivo as the C-50 for oxypurinol observed for 1MU/1MX r atio, plasma urate concentration and urine urate excretion rate were s imilar. 6 The concentration of oxypurinol required for inhibition of x anthine oxidase, as indicated by C-50 was lower than those often obser ved in clinical practice.