Impaired response or insufficient dosage? Examining the potential causes of "inadequate response" to allopurinol in the treatment of gout

Objectives: Gout is one of the most common forms of arthritis. It is well established that urate-lowering therapy that aims for a serum urate less than at least 0.36 mmol/l (6 mg/dl) is required for the successful management of gout. Allopurinol, a xanthine oxidase (XO) inhibitor, is the most commonly used urate-lowering therapy. However, many patients fail to achieve the target serum urate on allopurinol; these patients can be considered to have "inadequate response" to allopurinol. Herein, we examine the potential mechanisms and implications of inadequate response to allopurinol.

Methods: The literature was reviewed for potential causes for failure to reach target serum urate in patients receiving allopurinol.

Results: The two most common causes of inadequate response to allopurinol are poor adherence and under-dosing of allopurinol. Adherent patients who fail to achieve target serum urate on standard doses of allopurinol form a group that could be considered to be "partially resistant" to allopurinol. There are four potential mechanisms for partial allopurinol resistance: decreased conversion of allopurinol to oxypurinol; increased renal excretion of oxypurinol; abnormality in XO structure and/or function such that oxypurinol is rendered less effective and/or drug interactions.

Conclusions: It is important to determine the reasons for failure to achieve treatment targets with allopurinol, particularly as newer agents become available. The knowledge of the mechanisms for inadequate response may help guide the clinician towards making a therapeutic choice that is more likely to result in achieving the serum urate target.