From the Guidelines
In individuals with gout who are treated with allopurinol for long-term management, hypoxanthine and xanthine would most likely accumulate in the urine. This occurs because allopurinol works by inhibiting xanthine oxidase, the enzyme responsible for converting hypoxanthine to xanthine and subsequently xanthine to uric acid, as described in the study by 1. When this enzyme is blocked, the body cannot complete the final steps of purine metabolism, leading to decreased production of uric acid (which causes gout when it accumulates) and increased levels of the precursor molecules hypoxanthine and xanthine. Since these compounds are more water-soluble than uric acid, they are readily excreted in the urine rather than crystallizing in joints. This mechanism explains why allopurinol effectively reduces serum uric acid levels and prevents gout attacks, as it shifts the metabolic pathway toward producing more soluble purine metabolites that can be eliminated through the kidneys, as supported by the guidelines outlined in 1 and 1. The most recent and highest quality study, 1, confirms that allopurinol is recommended as first-line urate-lowering therapy (ULT) and its dosage should be adjusted according to renal function, further supporting the conclusion that hypoxanthine and xanthine accumulate in the urine. Key points to consider include:
- Allopurinol inhibits xanthine oxidase, blocking the conversion of hypoxanthine to xanthine and xanthine to uric acid
- This leads to increased levels of hypoxanthine and xanthine, which are more water-soluble than uric acid
- Hypoxanthine and xanthine are readily excreted in the urine, rather than crystallizing in joints
- Allopurinol effectively reduces serum uric acid levels and prevents gout attacks by shifting the metabolic pathway toward producing more soluble purine metabolites.
From the FDA Drug Label
Allopurinol is an inhibitor of xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid, the end product of purine metabolism in man. The renal clearance of hypoxanthine and xanthine is at least 10 times greater than that of uric acid The increased xanthine and hypoxanthine in the urine have not been accompanied by problems of nephrolithiasis.
The bases that most likely would accumulate in urine in individuals with gout given allopurinol are Hypoxanthine and Xanthine 2.
From the Research
Accumulation of Bases in Urine
In individuals with gout given allopurinol for long-term management, the following bases are likely to accumulate in urine:
- Hypoxanthine and xanthine The reason for this accumulation is due to the mechanism of action of allopurinol, which inhibits the enzyme xanthine oxidase, preventing the conversion of hypoxanthine to xanthine and xanthine to uric acid 3, 4, 5, 6.
Mechanism of Allopurinol
Allopurinol works by inhibiting xanthine oxidase, an enzyme responsible for the conversion of hypoxanthine to xanthine and xanthine to uric acid 4, 5, 6. As a result, the levels of hypoxanthine and xanthine increase, leading to their accumulation in urine.
Clinical Implications
The accumulation of hypoxanthine and xanthine in urine can lead to the formation of xanthine stones, which may require dose adjustments of allopurinol to prevent excessive oxypurine excretion rates 3. Additionally, the inhibition of xanthine oxidase by allopurinol can have beneficial effects on cardiovascular health by reducing the formation of radical oxygen species and improving myocardial efficiency 7.
Key Findings
Key findings from the studies include:
- Allopurinol increases mean hypoxanthine and xanthine urinary excretion rates 5.4- and 9.5-fold, respectively, compared with baseline levels 3
- The decrease in uric acid excretion is not accompanied by a stoichiometric substitution of hypoxanthine and xanthine excretion rates 3
- Allopurinol is efficacious and generally safe for the treatment of uric acid overproduction in patients with HPRT deficiencies 3