Urinorm Mechanism of Action

Pharmacology: Pharmacodynamics: Febuxostat inhibits xanthine oxidase, the enzyme that catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid. By blocking uric acid production, febuxostat decreases serum concentrations of uric acid. Febuxostat is not expected to inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at therapeutic concentrations.
In healthy subjects, febuxostat resulted in a dose dependent decrease in 24-hour mean serum uric acid concentrations and an increase in 24-hour mean serum xanthine concentrations. There was also a decrease in the total daily urinary uric acid excretion and an increase in total daily urinary xanthine excretion. Percent reduction in 24-hour mean serum uric acid concentrations was between 40 to 55% at the exposure levels of 40 mg and 80 mg daily doses.
Pharmacokinetics: Maximum plasma concentrations (C_max) and area under the curve (AUC) of febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg to 120 mg in healthy subjects. There is no accumulation when therapeutic doses are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t_1/2) of approximately 5 to 8 hours. The pharmacokinetic parameters of febuxostat for patients with hyperuricemia and gout were similar to those estimated in healthy subjects.
The absorption of radiolabeled febuxostat following oral dose administration was estimated to be at least 49% with maximum plasma concentrations occurring between 1 to 1.5 hours post-dose. After multiple oral 40 mg and 80 mg once daily doses, C_max is approximately 1.6 ± 0.6 mcg per mL, and 2.6 ± 1.7 mcg per mL, respectively. The absolute bioavailability of febuxostat tablet has not been studied.
Following multiple 80 mg once daily doses with a high fat meal, there was a 49% decrease in C_max and an 18% decrease in AUC, respectively. However, no clinically significant change in the percent decrease in serum uric acid concentration was observed.
Concomitant ingestion of an antacid containing magnesium hydroxide and aluminum hydroxide with an 80 mg single dose of febuxostat has been shown to delay absorption of febuxostat (approximately 1 hour) and to cause a 31% decrease in C_max and a 15% decrease in AUC_∞. As AUC rather than C_max was related to drug effect, change observed in AUC was not considered clinically significant.
The mean apparent steady state volume of distribution (V_ss/F) of febuxostat was approximately 50 L. The plasma protein binding of febuxostat is approximately 99.2%, primarily to albumin, and is constant over the concentration range achieved with 40 mg and 80 mg doses.
Febuxostat is extensively metabolized by both conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes including UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and oxidation via cytochrome P450 (CYP) enzymes including CYP1A2, 2C8 and 2C9 and non-P450 enzymes. The oxidation of the isobutyl side chain leads to the formation of four pharmacologically active hydroxy metabolites, all of which occur in human plasma at a much lower extent than febuxostat.
The apparent mean terminal elimination half-life (t_1/2) of febuxostat is approximately 5 to 8 hours.
In urine and feces, acyl glucuronide metabolites of febuxostat and oxidative metabolites 67M-1, 67M-2, and 67M-4, a secondary metabolite from 67M-1, appeared to be the major metabolites of febuxostat in vivo.
Febuxostat is eliminated by both hepatic and renal pathways. Following an 80 mg oral dose of 14C-labeled febuxostat, approximately 49% of the dose was recovered in the urine as unchanged febuxostat (3%), the acyl glucuronide of the drug (30%), its known oxidative metabolites and their conjugates (13%), and other known metabolites (3%). Also, approximately 45% of the dose was recovered in feces as unchanged febuxostat (12%), the acyl glucuronide of the drug (1%), its known oxidative metabolites and their conjugates (25%), and other known metabolites (7%).