Relationship between plasma oxipurinol concentrations and xanthine oxidase activity in volunteers dosed with allopurinol.

1. 1‐methyl xanthine (1‐MX) is metabolized exclusively to 1‐methyl uric acid (1‐MU) by the enzyme xanthine oxidase. 2. The ratio of 1‐MU to 1‐ MX in the urine, following a dose of 50 mg of 1‐MX infused intravenously over 20 min, was used to measure the inhibition of xanthine oxidase induced by different doses of allopurinol. 3. Normal volunteers (n = 8) were given allopurinol 50, 100, 300 and 600 mg daily for 1 week each, in random order and 1 week separated each treatment. Inhibition of xanthine oxidase was assessed twice, on the last 2 days of each treatment week. 4. Steady‐state oxipurinol concentrations increased linearly with increasing dose of allopurinol. 5. There was a hyperbolic relationship between the 1‐MU/1‐MX ratio and plasma oxipurinol concentrations, with an initial steep decline in the ratio which plateaued when plasma oxipurinol was around 4‐6 mg l‐1. This reduction in the ratio was quickly reversible upon cessation of allopurinol. 6. The 50% and 90% effective inhibitory oxipurinol concentrations, in relation to the 1‐MU‐/1‐MX ratio were 1.4 +/‐ 0.46 and 4.08 +/‐ 2.03 mg l‐1 respectively. 7. The concentration of oxipurinol required for almost complete inhibition of the enzyme was substantially less than those often observed in clinical practice. 1988 The British Pharmacological Society