Indications
Febuxostat is prescribed for the chronic management of hyperuricemia in adult patients suffering from gout, particularly when there is an inadequate response to a maximally titrated dose of allopurinol, intolerance to allopurinol, or when the use of allopurinol is deemed inappropriate. It is important to note that febuxostat is not recommended for treating asymptomatic hyperuricemia or secondary hyperuricemia.
Pharmacodynamics
As a selective inhibitor of xanthine oxidase/dehydrogenase, febuxostat functions by reducing serum uric acid levels in a dose-dependent manner. Clinical studies involving healthy subjects demonstrated that febuxostat effectively decreased mean serum uric acid and xanthine concentrations, alongside reducing total urinary uric acid excretion. Administration of febuxostat at daily doses ranging from 40 to 80 mg resulted in a reduction of 24-hour mean serum uric acid concentrations by approximately 40 to 55%. It is noteworthy that the reduction of serum uric acid levels, along with the mobilization of urate crystals in tissue deposits, can lead to gout flares associated with febuxostat usage. Unlike allopurinol and oxypurinol, febuxostat does not inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism, as it does not structurally resemble purines or pyrimidines.
Absorption
Upon oral administration, febuxostat is rapidly absorbed, with approximately 85% of the drug being absorbed into the system. The time to reach maximum plasma concentration (Tmax) ranges from 1 to 1.5 hours. In terms of peak plasma concentration (Cmax), a 40 mg dose of febuxostat achieves approximately 1.6 ± 0.6 mcg/mL, while an 80 mg dose results in approximately 2.6 ± 1.7 mcg/mL. While a high-fat meal can reduce the Cmax by 49% and the area under the curve (AUC) by 18%, these changes do not significantly impact febuxostat's effectiveness in reducing serum uric acid concentrations.
Metabolism
Febuxostat undergoes extensive liver metabolism facilitated by both UDP-glucuronosyltransferase (UGT) and Cytochrome P450 (CYP) enzymes. The precise contribution of each enzyme isoform to febuxostat metabolism is not fully understood. The UGT1A1, UGT1A3, UGT1A9, and UGT2B7 enzymes mediate the conjugation of febuxostat, which accounts for approximately 22-44% of the total dose metabolism, leading to the production of the acyl-glucuronide metabolite. Oxidation reactions, accounting for 2-8% of the dose metabolism, involve CYP1A2, CYP2C8, CYP2C9, and non-P450 enzymes, producing active metabolites such as 67M-1, 67M-2, and 67M-4. These metabolites may undergo further glucuronidation and sulfation, although hydroxy metabolites appear in much lower concentrations in human plasma compared to the parent drug.
Mechanism of Action
Febuxostat is a potent inhibitor of xanthine oxidoreductase (XOR), a key enzyme in human purine metabolism responsible for the production of uric acid. XOR catalyzes the oxidation of hypoxanthine to xanthine and subsequently to uric acid, playing a vital role in the pathogenesis of gout-a condition characterized by the deposition of monosodium urate crystals in joints and tissues due to hyperuricemia. By effectively binding with high affinity to the molecular channel leading to the molybdenum-pterin active site of XOR, febuxostat inhibits both its oxidase and dehydrogenase activities, surpassing the relatively weak competitive inhibition demonstrated by allopurinol. Under normal conditions, XOR exists predominantly in the dehydrogenase form, but it can convert to the oxidase form during inflammatory states, producing reactive oxygen species (ROS) such as peroxynitrite. These ROS contribute to vascular inflammation and dysfunction. Febuxostat's ability to inhibit both forms of XOR allows it to mitigate ROS formation, reducing oxidative stress and inflammation. This function is further supported by evidence from a rat model, where febuxostat attenuated oxidative stress and diminished renal ischemia-reperfusion injury.
