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The Differences in the Mechanisms of Action Between Allopurinol and Febuxostat

Summary:

  • In the majority of patients with gout, the mainstay of treatment for decreasing serum uric acid concentrations has been with inhibitors of xanthine oxidase (XO), such as allopurinol (Zyloprim; Aloprim) and febuxostat (Uloric) along with changes in diet and lifestyle, to achieve a target serum uric acid level of < 6 mg/dL. 
  • Allopurinol is a purine analogue that is subject to being metabolized by many enzymes involved in purine and pyrimidine synthesis metabolism, whereas febuxostat is not a purine analogue.
  • Allopurinol and its metabolites inhibit not only XO, but can also inhibit purine nucleoside phosphorylase (PNP) in purine metabolism and orotidine-5'-monophosphate decarboxylase (OMPDC), which are needed in the synthesis of pyrimidines that will eventually be used for both RNA and DNA synthesis.
  • Febuxostat is only an inhibitor of XO and does not influence the activity of other enzymes involved in purine or pyrimidine synthesis or metabolism.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Reviewers:
Jon D. Herrington, PharmD, BCPS, BCOP
Last Reviewed: October 2015

Explanation

  • Gout has not only been a medical problem for centuries, but is increasing in prevalence across the world.1-3  This increase in prevalence may be due to people living longer, changes in dietary patterns that have led to increases in obesity and development of metabolic syndrome.1,4  While not all patients who have hyperuricemia are symptomatic, it is well known that the concentration of serum uric acid directly correlates with the development of gout.5,6  Normally, the enzyme xanthine oxidase (XO) is needed to convert the purine base hypoxanthine to xanthine and xanthine to uric acid (see figure).5  When the uric acid levels increase beyond 7 mg/dL in men and 6 mg/dL in postmenopausal females, the risk for precipitation of crystals can occur.5,6  For the majority of patients, the mainstay of treatment for decreasing serum uric acid concentrations has been with inhibitors of XO, such as allopurinol (Zyloprim; Aloprim) and febuxostat (Uloric), along with changes in diet and lifestyle, to achieve a target serum uric acid level of < 6 mg/dL.7,8 

    Do allopurinol and febuxostat inhibit XO differently?
    Yes. As stated above, hypoxanthine is a product generated in the metabolism of purines (guanine and cytosine) and, in the presence of functional XO, is metabolized to xanthine and again to uric acid where it then be eliminated primarily in the urine.5  Therefore, an analogue (something structurally similar) of purines can then compete with hypoxanthine and xanthine for metabolism by XO.  This is primarily where allopurinol and febuxostat are different.  Allopurinol and its metabolites are structural analogues of both purines and pyrimidines and thus can affect enzymes in both purine and pyrimidine metabolic pathways, whereas febuxostat is a non-purine inhibitor of XO only.7-11

                

    How does allopurinol influence more than XO activity?
    Since allopurinol is a purine analogue, it also undergoes metabolism by XO, which results in the production to its most active metabolite (oxypurinol).7,12  It is the oxypurinol that binds very tightly to the reduced form of XO, resulting in a suicide inhibition of XO.12  In addition, allopurinol is also metabolized by the enzymes hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and orotate phosphoribosyltransferase (OPRT) that result in the production of nucleotide analogues.9-11,13  Unfortunately, these metabolites can also inhibit purine nucleoside phosphorylase (PNP) in purine metabolism and orotidine-5'-monophosphate decarboxylase (OMPDC), which are needed in the synthesis of pyrimidines that will eventually be used for both RNA and DNA synthesis.10,14-16  It has been speculated that allopurinol's influence on these other pathways may be linked to some of allopurinol's side effects.  Since febuxostat is not a structural analogue of either purines or pyrimidines, it does not interfere with the activity of these other pathways.8,17  As such, it is a specific inhibitor of XO only.17  While febuxostat is a potent inhibitor of XO, it does so by inhibiting both the reduced and oxidized forms of XO, which is another difference from allopurinol. 

    Do these pharmacologic principles translate into any differences in the reduction of serum uric acid levels?
    Several studies comparing the most commonly used doses of allopurinol at 300 mg daily, showed the febuxostat, at mainly 80 mg, resulted in a greater percentage of patients being able to achieve serum uric acid levels < 6 mg/dL (allopurinol, 42% versus febuxostat, 72%).8    

    While not specifically related to the mechanism of action in gout, febuxostat, unlike allopurinol, is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1, 1A3, 1A9, 2B7 and cytochrome P-450 (CYP) 1A2, 2C8, and 2C9.8  In addition, febuxostat is also known to be a weak inhibitor of CYP2D6.8 As such, febuxostat may be subject to more drug interactions than compared to allopurinol.  However, it is imperative that clinicians recognize that both allopurinol and febuxostat can inhibit the XO-mediated metabolism of azathioprine (Imuran), thereby putting patients at an increased risk for life-threatening bone marrow suppression.7,8,18  Lastly, febuxostat also differs from allopurinol in that dose reductions are not needed in patients with mild to moderate renal impairment, whereas allopurinol does need dose reductions.8

    References:

    1. Bieber JD, Terkeltaub RA.  Gout: on the brink of novel therapeutic options for an ancient disease.  Arthritis Rheum  2004;50:2400-14.  
    2. Wallace KL, Reidel AA, Joseph-Ridge N et al.  Increasing prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population.  J Rheumatol  2004;31:1582-7.  
    3. Choi HK, Curhan G.  Gout: epidemiology and lifestyle choices.  Curr Opin Rheumatol  2005;17:341-5.  
    4. Johnson RJ, Rideout BA.  Uric acid and diet-insights into the epidemic of cardiovascular disease.  N Engl J Med  2004;350:1071-3.  
    5. Choi HK, Mount DB, Reginato AM et al.  Pathogenesis of gout.  Ann Intern Med  2005;143:499-516.  
    6. Terkeltaub RA.  Clinical practice.  Gout.  N Engl J Med  2003;349:1647-55. 
    7. Allopurinol tablets product package insert.  Watson Laboratories, inc.; Corona, CA.  January 2006.
    8. Febuxostat (UloricĀ®) product package insert.  Takeda Pharmaceuticals America, Inc.  Deerfield, IL.  February 2009.
    9. Reiter S, Loffler W, Grobner W et al.  Urinary oxipurinol-1-riboside excretion and allopurinol-induced oroticaciduria.  Adv Exp Med Biol  1986;195 Pt A:453-60.  
    10. Simmonds HA, Reiter S, Davies PM et al.  Orotidine accumulation in human erythrocytes during allopurinol therapy: association with high urinary oxypurinol-7-riboside concentrations in renal failure and in the Lesch-Nyhan syndrome.  Clin Sci (Lond)  1991;80:191-7.  
    11. Krenitsky TA, Elion GB, Strelitz RA et al.  Ribonucleosides of allopurinol and oxoallopurinol.  Isolation from human urine, enzymatic synthesis, and characterization.  J Biol Chem  1967;242:2675-82.  
    12. Massey V, Komai H, Plamer G et al.  On the mechanism of inactivation of xanthine oxidase by allopurinol and other pyrazolo[3,4-d]pyrimidines.  J Biol Chem  1970;245:2837-44.  
    13. Nelson DJ, Elion GB.  Metabolic studies of high doses of allopurinol in humans.  Adv Exp Mol Biol  1984;165 Pt A:167-70.  
    14. Krenitsky TA, Elion GB, Henderson AM et al.  Inhibition of human purine nucleoside phosphorylase.  Studies with intact erythrocytes and the purified enzyme.  J Biol Chem  1968;243:2876-81.  
    15. Nishida Y, Kamatani M, Tanimoto K et al.  Inhibition of purine nucleoside phosphorylase activity and of T-cell function with allopurinol-riboside.  Agents Actions  1979;9:549-52.  
    16. Kelley WN, Beardmore TD.  Allopurinol: alteration in pyrimidine metabolism in man.  Science  1970;169:388-90.  
    17. Komoriya K, Hoshide S, Takeda K et al.  Pharmacokinetics and pharmacodynamics of febuxostat (TMX-67), a non-purine selective inhibitor of xanthine oxidase/xanthine dehydrogenase (NPSIXO) in patients with gout and/or hyperuricemia.  Nucleoside Nucleotides Nucleic Acids  2004;23:1119-22.  
    18. Busti AJ, Lehew DS, Nuzum DS et al.  How does the interaction between allopurinol (Zyloprim, Aloprim) and the immunosuppressant, azathioprine (Imuran; Azasan) increase the risk of significant reductions in WBCs? Pw Database.

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MESH Terms & Keywords

  • Allopurinol, Zyloprim, Aloprim, Febuxostat, Uloric, Allopurinol Mechanism of Action, Febuxostat Mechanism of Action