A 55-year-old man with gout refractory to colchicine and NSAIDs is started on pegloticase. The molecular mechanism of pegloticase differs from all other urate-lowering therapies because it:

• A Selectively inhibits URAT1 (urate-anion transporter 1) in the proximal tubule, promoting urate excretion
• B Is PEGylated recombinant porcine-derived uricase (urate oxidase) that converts urate to allantoin (a water-soluble metabolite excreted in urine), bypassing the missing human uricase enzyme ✓
• C Inhibits xanthine oxidase non-competitively by binding the molybdenum cofactor irreversibly
• D Inhibits the NLRP3 inflammasome, preventing IL-1beta maturation in response to urate crystals

Explanation

Pegloticase is PEGylated recombinant urate oxidase (uricase), an enzyme that humans genetically lack (due to mutations in the uricase gene that occurred during primate evolution). It converts uric acid to allantoin, which is 5-10 times more soluble and is easily renally excreted, rapidly reducing tophus burden. PEGylation extends its half-life and reduces immunogenicity. Anti-drug antibodies remain problematic and require monitoring. This mechanism is fundamentally different from xanthine oxidase inhibitors (allopurinol, febuxostat) which block urate synthesis, or URAT1 inhibitors (lesinurad, benzbromarone) which increase renal urate excretion.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.