On the Mechanism of Inactivation of Xanthine Oxidase by Allopurinol and Other Pyrazolo[3,4-d]pyrimidines

Massey, Vincent; Komai, Hirochika; Palmer, Graham; Elion, Gertrude B.

doi:10.1016/s0021-9258(18)63065-0

Cited by 365 publications

(82 citation statements)

References 17 publications

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“…The K d (dissociation constant) for oxypurinol with the human XOR is 8.6 µM [49]. The oxypurinol-XOR complex cleaves spontaneously with a short halflife of 5 h at 25 °C [50] and a half-life of only 39 minutes at 37 °C [49]. Both allopurinol and oxypurinol are purine derivatives (Figure 1.1b and c) and they were found to inhibit additional enzymes involved in the purine and pyrimidine metabolism [51].…”

Section: In Vitro Pharmacodynamics Of Allopurinolmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Febuxostat

et al. 2016

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Febuxostat is a xanthine oxidoreductase inhibitor that has been developed to treat chronic gout. In healthy subjects, the pharmacokinetic parameters of febuxostat after multiple oral dose administration include an oral availability of about 85 %, an apparent oral clearance (CL/F) of 10.5 ± 3.4 L/h and an apparent volume of distribution at steady state (V /F) of 48 ± 23 L. The time course of plasma concentrations follows a two-compartment model. The initial half-life (t) is approximately 2 h and the terminal t determined at daily doses of 40 mg or more is 9.4 ± 4.9 h. Febuxostat is administered once daily. The maximum (peak) plasma concentrations are approximately 100-fold greater than the trough concentrations. Consequently, there is no significant accumulation of the drug during multiple dose administration. There are few data on the pharmacokinetics of febuxostat in patients with gout. While the pharmacokinetic parameters are not affected by mild to moderate hepatic impairment, there is no consensus on whether renal impairment has any effect on the pharmacokinetics of febuxostat. Febuxostat is extensively metabolised by oxidation (approximately 35 %) and acyl glucuronidation (up to 40 %); febuxostat acyl glucuronides are cleared by the kidney. In healthy subjects treated with multiple doses of febuxostat 10-240 mg, the concentrations of serum urate are reduced by a maximum of about 80 %. The percentage reduction in the concentrations of serum urate is slightly less in gouty patients than in healthy subjects.

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Section: In Vitro Pharmacodynamics Of Allopurinolmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Febuxostat

et al. 2016

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“…43 Furthermore, allopurinol and oxypurinol bind tightly to the reduced form of xanthine oxidoreductase, but they only weakly and transiently inhibit the oxidized form; thus, these drugs may lower uric acid but not blunt the generation of superoxide anion by xanthine oxidase. 44,45 To complicate matters further, allopurinol and oxypurinol inhibit not only xanthine oxidoreductase, but also other purine-and pyrimidine-metabolizing enzymes. 46,47 In contrast, febuxostat acts selectively on xanthine oxidoreductase, 48 binds tightly to the oxidized form, and, thus, inhibits xanthine oxidase more effectively than allopurinol 49 ; yet, febuxostat increases cardiovascular risk more than allopurinol.…”

Section: Xanthine Oxidase As a Generator Of Oxidative Stressmentioning

confidence: 99%

Uric Acid Is a Biomarker of Oxidative Stress in the Failing Heart: Lessons Learned from Trials With Allopurinol and SGLT2 Inhibitors

Packer

2020

Journal of Cardiac Failure

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Hyperuricemia increases the risk of heart failure, and higher levels of serum uric acid are seen in patients who have worse ventricular function, functional capacity, and prognosis. Heart failure is also accompanied by an upregulation of xanthine oxidase, the enzyme that catalyzes the formation of uric acid and a purported source of reactive oxygen species. However, the available evidence does not support the premise that either uric acid or the activation of xanthine oxidase has direct injurious effects on the heart in the clinical setting. Xanthine oxidase inhibitors (allopurinol and oxypurinol) have had little benefit and may exert detrimental effects in patients with chronic heart failure in randomized controlled trials, and the more selective and potent inhibitor febuxostat increases the risk of cardiovascular death more than allopurinol. Instead, the available evidence indicates that changes in xanthine oxidase and uric acid are biomarkers of oxidative stress (particularly in heart failure) and that xanthine oxidase may provide an important source of nitric oxide that quenches the injurious effects of reactive oxygen species. A primary determinant of the cellular redox state is nicotinamide adenine dinucleotide, whose levels drive an inverse relationship between xanthine oxidase and sirtuin-1, a nutrient deprivation sensor that exerts important antioxidant and cardioprotective effects. Interestingly, sodium-glucose cotransporter 2 inhibitors induce a state of nutrient deprivation that includes activation of sirtuin-1, suppression of xanthine oxidase, and lowering of serum uric acid. The intermediary role of sirtuin-1 in both uric acid-lowering and cardioprotection may explain why, in mediation analyses of large-scale cardiovascular trials, the effect of sodium-glucose cotransporter 2 inhibitors to decrease serum uric acid is a major predictor of the ability of these drugs to decrease serious heart failure events.

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“…The C2 of allopurinol is hydroxylated and converted to oxypurinol. In the course of the reaction, the transiently generated reduced Mo(IV) and N8 of oxypurinol form a covalent bond ( Figure 4 A) [ 33 , 34 ]. In this process, oxypurinol is thought to form a complex efficiently by rotating in the substrate-binding pocket.…”

Section: Inhibition Mechanisms Of the Inhibitorsmentioning

confidence: 99%

Association of Mutations Identified in Xanthinuria with the Function and Inhibition Mechanism of Xanthine Oxidoreductase

Sekine

Ichida

2021

Biomedicines

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Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the two-step reaction from hypoxanthine to xanthine and from xanthine to uric acid in purine metabolism. XOR generally carries dehydrogenase activity (XDH) but is converted into an oxidase (XO) under various pathophysiologic conditions. The complex structure and enzymatic function of XOR have been well investigated by mutagenesis studies of mammalian XOR and structural analysis of XOR–inhibitor interactions. Three XOR inhibitors are currently used as hyperuricemia and gout therapeutics but are also expected to have potential effects other than uric acid reduction, such as suppressing XO–generating reactive oxygen species. Isolated XOR deficiency, xanthinuria type I, is a good model of the metabolic effects of XOR inhibitors. It is characterized by hypouricemia, markedly decreased uric acid excretion, and increased serum and urinary xanthine concentrations, with no clinically significant symptoms. The pathogenesis and relationship between mutations and XOR activity in xanthinuria are useful for elucidating the biological role of XOR and the details of the XOR reaction process. In this review, we aim to contribute to the basic science and clinical aspects of XOR by linking the mutations in xanthinuria to structural studies, in order to understand the function and reaction mechanism of XOR in vivo.

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On the Mechanism of Inactivation of Xanthine Oxidase by Allopurinol and Other Pyrazolo[3,4-d]pyrimidines

Cited by 365 publications

References 17 publications

Clinical Pharmacokinetics and Pharmacodynamics of Febuxostat

Clinical Pharmacokinetics and Pharmacodynamics of Febuxostat

Uric Acid Is a Biomarker of Oxidative Stress in the Failing Heart: Lessons Learned from Trials With Allopurinol and SGLT2 Inhibitors

Association of Mutations Identified in Xanthinuria with the Function and Inhibition Mechanism of Xanthine Oxidoreductase

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