Mechanism of Action of Rasburicase
Rasburicase is a recombinant urate oxidase enzyme that catalyzes the enzymatic oxidation of poorly soluble uric acid into allantoin, an inactive metabolite that is 5-10 times more soluble in urine than uric acid and readily excreted by the kidneys. 1, 2
Biochemical Pathway
Rasburicase directly degrades existing uric acid through enzymatic oxidation, converting it to allantoin—a compound with dramatically enhanced renal solubility and clearance 1, 2
The enzyme was cloned from Aspergillus flavus and expressed in a modified Saccharomyces cerevisiae strain, yielding a recombinant protein with a molecular mass of approximately 34 kDa 2
This mechanism fundamentally differs from xanthine oxidase inhibitors (allopurinol, febuxostat), which only prevent new uric acid formation but cannot eliminate pre-existing hyperuricemia 2, 3
Clinical Pharmacodynamics
Rasburicase achieves an 86% reduction in plasma uric acid within 4 hours of the first dose, compared to only 12% reduction with allopurinol over the same timeframe 2, 4
Following administration of 0.15-0.20 mg/kg daily, plasma uric acid levels decrease within 4 hours and are maintained below 7.5 mg/dL in 98% of adult patients and 90% of pediatric patients for at least 7 days 1
The mean terminal half-life ranges from 15.7 to 22.5 hours, with minimal drug accumulation (<1.3-fold) between days 1 and 5 of dosing 1, 2
Critical Distinction from Allopurinol
Rasburicase acts on existing uric acid stores, while allopurinol only blocks future production—this is why rasburicase is superior in acute tumor lysis syndrome where immediate reduction of pre-existing hyperuricemia is life-saving. 2, 3
In randomized trials, rasburicase achieved a mean uric acid area-under-the-curve of 128±70 mg·dL⁻¹·hour versus 329±129 mg·dL⁻¹·hour with allopurinol (p<0.001) 3
A retrospective pediatric study demonstrated that only 2.6% of patients receiving rasburicase required dialysis compared to 16% receiving allopurinol 3, 4
Important Mechanistic Considerations
Rasburicase should never be administered concurrently with xanthine oxidase inhibitors (allopurinol or febuxostat), because blocking xanthine oxidase causes accumulation of xanthine and hypoxanthine—the substrates rasburicase needs to function—and these poorly soluble purines can crystallize in renal tubules causing obstructive uropathy 5, 3
The enzyme continues to degrade uric acid ex vivo in blood samples at room temperature, so specimens must be immediately placed on ice and assayed within 4 hours to avoid falsely low measurements 5, 3
Rasburicase is contraindicated in glucose-6-phosphate dehydrogenase (G6PD) deficiency because the hydrogen peroxide generated during uric acid oxidation can trigger life-threatening hemolysis and methemoglobinemia in these patients 5, 3