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Pharmacology: Pharmacodynamics: Allopurinol is a structural analogue of hypoxanthine, the natural purine base. Allopurinol and its active metabolite oxipurinol (alloxanthine), lower uric acid levels in plasma and urine by inhibiting xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and from xanthine to uric acid, the end product of purine metabolism. Inhibition of this enzyme accounts for the major pharmacological effects of allopurinol.
In addition, allopurinol increases reutilization of oxypurine precursors eg, hypoxanthine and xanthine for nucleotide and nucleic acid synthesis via an action involving the enzyme hypoxanthine-guanine phosphorbosyltransferase (HGPRTase). The increase in nucleotide concentration leads to feedback inhibition of de novo purine synthesis. In this way, allopurinol decreases uric acid concentrations in both serum and urine.
Thus, allopurinol reduces the plasma concentration and urinary excretion of uric acid and increases the plasma concentration and renal excretion of the more soluble oxypurine precursors.
Pharmacokinetics: Allopurinol is rapidly absorbed from the upper gastrointestinal tract after oral administration. Mean bioavailability varies from 67-90%. Allopurinol peak serum levels occur approximately 1.5 hrs after oral administration, but fall rapidly and are barely detectable after 6 hrs. Peak serum levels of oxipurinol occur within 3-5 hrs after oral dosing and are more sustained.
Allopurinol is negligibly bound to plasma proteins and therefore, variations in protein-binding are not thought to significantly alter clearance. Allopurinol's apparent volume of distribution is approximately 1.6 L/kg, which suggests relatively extensive uptake by tissues. Tissue concentrations of allopurinol have not been reported in humans, but it is likely that allopurinol and oxipurinol will be present in the highest concentrations in the liver and intestinal mucosa where xanthine oxidase activity is high. There is gradual accumulation of oxipurinol with continued administration of allopurinol in patients with normal renal function. Serum oxipurinol levels in such patients are in the range of 5-10 mg/L on a daily dose of allopurinol 300 mg. At steady-state, comparable peak allopurinol levels are between 1.5-2 mg/L. The area under the curve (AUC) determination for oxipurinol is approximately 20-fold greater than that of allopurinol over a 24-hr period. Allopurinol and its metabolites have been detected in human milk.
Approximately 20% of an allopurinol dose is excreted in the feces in 48-72 hrs. Elimination of allopurinol is mainly by metabolic conversion to oxipurinol (in the liver and probably also in the intestines) by xanthine oxidase and aldehyde oxidase, with <10% of unchanged drug excreted in the urine. Allopurinol has a plasma half-life (t½) of about 1-2 hrs. Oxipurinol is eliminated unchanged in the urine but has a long elimination t½ (13.6-29 hrs) because it undergoes tubular reabsorption. Allopurinol is cleared essentially by glomerular filtration, however, oxipurinol is reabsorbed in the kidney tubules in a manner similar to the reabsorption of uric acid.
Special Population: Renal Insufficiency: Elimination of both allopurinol and oxipurinol is delayed in patients with kidney impairment resulting in higher plasma levels with chronic therapy. A reduction in dose is required. (See Precautions.)
Hepatic Insufficiency: The clearance of allopurinol may be reduced in patients with liver disease. A reduction in dose is required. (See Precautions.)
Elderly: The kinetics of allopurinol in elderly patients is not likely to be altered other than due to deteriorating renal function. (See Precautions.)
