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.
Day
R O
RO
Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Darlinghurst, Sydney, Australia.
Miners
J
J
Birkett
D J
DJ
Graham
G G
GG
Whitehead
A
A
D000328:Adult; D000493:Allopurinol / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D010117:Oxypurinol / Q000097:blood*; D011743:Pyrimidines / Q000097:blood*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000097:blood*
D011743:Pyrimidines; D000493:Allopurinol; D014969:Xanthine Oxidase; D010117:Oxypurinol