oxypurinol and Gout

Allopurinol, a first line urate-lowering therapy, has been associated with serious cutaneous reactions that have a high mortality. A number of risk factors for these serious adverse reactions have been identified including ethnicity, HLA-B∗5801 genotype, kidney impairment, allopurinol starting dose, and concomitant diuretic use. There is a complex interplay between these risk factors, which may (albeit rarely) lead to allopurinol-related serious adverse events. Although oxypurinol, the active metabolite of allopurinol, has been implicated, there is no defined drug concentration at which the reaction will occur. There is no specific treatment other than the cessation of allopurinol and supportive care. Whether hemodialysis, which rapidly removes oxypurinol, improves outcomes remains to be determined. Strategies to help reduce this risk are therefore important, which includes screening for HLA-B∗5801 in high-risk individuals, commencing allopurinol at low dose, and educating patients about the signs and symptoms of severe cutaneous adverse reactions, and what to do if they occur.

Topics: Allopurinol; Drug Hypersensitivity; Gout; Gout Suppressants; Humans; Oxypurinol

Allopurinol is the most commonly prescribed urate-lowering therapy for the management of gout. Serious adverse reactions associated with allopurinol, while rare, are feared owing to the high mortality. Such reactions can manifest as a rash combined with eosinophilia, leukocytosis, fever, hepatitis and progressive kidney failure. Risk factors for allopurinol-related severe adverse reactions include the recent introduction of allopurinol, the presence of the HLA-B(*)58:01 allele, and factors that influence the drug concentration. The interactions between allopurinol, its metabolite, oxypurinol, and T cells have been studied, and evidence exists that the presence of the HLA-B(*)58:01 allele and a high concentration of oxypurinol function synergistically to increase the number of potentially immunogenic-peptide-oxypurinol-HLA-B(*)58:01 complexes on the cell surface, thereby increasing the risk of T-cell sensitization and a subsequent adverse reaction. This Review will discuss the above issues and place this in the clinical context of reducing the risk of serious adverse reactions.

Topics: Allopurinol; Drug Hypersensitivity; Drug Hypersensitivity Syndrome; Genetic Testing; Gout; HLA-B Antigens; Kidney; Oxypurinol; Skin; T-Lymphocytes

Allopurinol, the first-line drug for serum urate-lowering therapy in gout, is approved by the US Food and Drug Administration for a dose up to 800 mg/d and is available as a low-cost generic drug. However, the vast majority of allopurinol prescriptions are for doses < or = 300 mg/d, which often fails to adequately treat hyperuricemia in gout. This situation has been promoted by longstanding, non-evidence-based guidelines for allopurinol use calibrated to renal function (and oxypurinol levels) and designed, without proof of efficacy, to avoid allopurinol hypersensitivity syndrome. Severe allopurinol hypersensitivity reactions are not necessarily dose-dependent and do not always correlate with serum oxypurinol levels. Limiting allopurinol dosing to < or = 300 mg/d suboptimally controls hyperuricemia and fails to adequately prevent hypersensitivity reactions. However, the long-term safety of elevating allopurinol dosages in chronic kidney disease requires further study. The emergence of novel urate-lowering therapeutic options, such as febuxostat and uricase, makes timely this review of current allopurinol dosing guidelines, safety, and efficacy in gout hyperuricemia therapy, including patients with chronic kidney disease.

Topics: Allopurinol; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Hypersensitivity; Gout; Gout Suppressants; Health Care Costs; Humans; Hyperuricemia; Kidney; Kidney Function Tests; Oxypurinol; Practice Guidelines as Topic

The spectrum of kidney and urinary tract disorders related to purines comprises acute hyperuricosuric nephropathy, chronic urate nephropathy and urolithiasis. Two factors in the development of acute hyperuricosuric nephropathy are increased uric acid concentration and low pH in the tubular fluid. Chronic urate nephropathy still possess several problems: incidence (although this seems to be decreasing, presumably owing to effective prevention), the source of interstitial urate, the cause of the interstitial deposition of urate, and the role of urate deposits in the pathogenesis of the interstitial nephropathy. The relation of the experimental nephropathy to the pathogenesis of chronic urate nephropathy in the human is not yet clear but a model is proposed according to which interstitial urate derives from two sources: hyperuricaemic plasma and hyperuricosuric tubular fluid. Urolithiasis related to purines leads to uric acid-urate stones, xanthine stones, 2,8-dihydroxyadenine stones, iatrogenic xanthine and oxipurinol stones, and possibly calcium stones. Pathogenetic factors in uric acid lithiasis are hyperuricosuria (whether due to an inborn enzyme abnormality or of unknown aetiology) and low urinary pH; oliguria is a contributory factor. There remain several open questions about uric acid lithiasis: incidence, the shift of its location from lower to upper urinary tract, the interplay of pathogenetic factors, and the role of compounds which inhibit crystallization.

Topics: Adenine Phosphoribosyltransferase; Allopurinol; Animals; Calcium; Gout; Humans; Hydrogen-Ion Concentration; Hypoxanthine Phosphoribosyltransferase; Kidney Calculi; Kidney Diseases; Kidney Failure, Chronic; Oxypurinol; Purines; Sodium; Solubility; Uric Acid; Urologic Diseases; Xanthine Oxidase; Xanthines

The aims of this study were to determine factors that predict serum urate (SU) lowering response to allopurinol and the conversion of allopurinol to oxypurinol, and to determine a minimum therapeutic oxypurinol concentration. Data from 129 participants in a 24-month open, randomized, controlled, parallel-group, comparative clinical trial were analyzed. Allopurinol dose, SU, and plasma oxypurinol concentrations were available at multiple time points. The slope for the association between allopurinol dose and SU was calculated as a measure of sensitivity to allopurinol. The slope for the association between allopurinol dose and oxypurinol was calculated as a measure of allopurinol metabolism. Receiver operating characteristic (ROC) curves were used to identify a minimum oxypurinol concentration predictive of SU < 6 mg/dL. There was a wide range of SU concentrations for each allopurinol dose. The relationship between sensitivity to allopurinol and allopurinol metabolism for each 100 mg allopurinol dose increase varied between individuals. Body mass index (P = 0.023), creatinine clearance (CrCL; P = 0.037), ABCG2 Q141K (P = 0.019), and SU (P = 0.004) were associated with sensitivity to allopurinol. The minimum oxypurinol concentration for achieving the urate target was found to be about 104 μmol/L, but predictive accuracy was poor (ROC curve area under the curve (AUC) 0.65). The minimum therapeutic oxypurinol concentration was found to increase with decreasing renal function. Although there is a positive relationship between change in oxypurinol and change in SU concentration, a minimum therapeutic oxypurinol is dependent on CrCL and cannot reliably predict SU target. Other variables, including ABCG2 Q141K genotype, impact on sensitivity to allopurinol (ACTRN12611000845932).

Topics: Aged; Allopurinol; ATP Binding Cassette Transporter, Subfamily G, Member 2; Body Mass Index; Creatinine; Dose-Response Relationship, Drug; Female; Gout; Gout Suppressants; Humans; Male; Middle Aged; Neoplasm Proteins; Oxypurinol; Renal Elimination; ROC Curve; Treatment Outcome; Uric Acid

Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for treatment of hyperuricemia and gout. This phase 1b, multiple-dose, drug-drug interaction study evaluated the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in combination with allopurinol. Adult males with gout were randomized to receive once-daily oral doses of allopurinol 300 mg or verinurad 10 mg alone for 7 days, allopurinol 300 mg + verinurad 10 mg on days 8 to 14, and the alternative single agent on days 15 to 21. Colchicine 0.6 mg was taken prophylactically for gout flares. Plasma/serum and urine samples were assayed for verinurad, allopurinol, oxypurinol (allopurinol active metabolite), colchicine (plasma only), and uric acid. Safety was assessed by adverse events (AEs) and laboratory tests. Verinurad plasma exposure was unaffected by allopurinol. Verinurad increased the maximum observed plasma concentration (C

Topics: Adolescent; Adult; Aged; Allopurinol; Area Under Curve; Drug Administration Schedule; Gout; Gout Suppressants; Humans; Male; Middle Aged; Naphthalenes; Oxypurinol; Propionates; Pyridines; Uric Acid; Young Adult

To determine the effects of furosemide on serum urate (SU), plasma oxypurinol and urinary urate.. Twenty-three cases with gout receiving furosemide and allopurinol were recruited. Twenty-three controls with gout receiving allopurinol but no diuretics were matched on age, gender, estimated glomerular filtration rate and allopurinol dose. SU, plasma oxypurinol and urinary urate were assessed on a single occasion. The effects of a single dose of furosemide 40 mg were examined in a separate group of 10 patients receiving allopurinol but not diuretic.. Cases had significantly higher SU and plasma oxypurinol compared with controls despite receiving similar doses of allopurinol. There was no difference in urinary urate excretion. There was a significant increase in area under the curve (AUC)(0-24) for oxypurinol after administration of furosemide 40 mg.. The interaction between allopurinol and furosemide results in increased SU and plasma oxypurinol. The exact mechanisms remain unclear but complex interactions that result in attenuation of the hypouricaemic effects of oxypurinol are likely.. Australian New Zealand Clinical Trials Registry, www.anzctr.org.au, 12609000529246.

Topics: Adult; Aged; Allopurinol; Area Under Curve; Case-Control Studies; Diuretics; Drug Interactions; Drug Therapy, Combination; Female; Furosemide; Gout; Gout Suppressants; Humans; Male; Middle Aged; Oxypurinol; Treatment Outcome; Uric Acid; Urination

To investigate the pharmacokinetic and pharmacodynamic interaction between probenecid and oxypurinol (the active metabolite of allopurinol) in patients with gout.. This was an open-label observational clinical study. Blood and urine samples were collected to measure oxypurinol and urate concentrations. We examined the effects of adding probenecid to allopurinol therapy upon plasma concentrations and renal clearances of urate and oxypurinol.. Twenty patients taking allopurinol 100-400 mg daily completed the study. Maximum coadministered doses of probenecid were 250 mg/day (n = 1), 500 mg/day (n = 19), 1000 mg/day (n = 7), 1500 mg/day (n = 3), and 2000 mg/day (n = 1). All doses except the 250 mg daily dose were divided and dosing was twice daily. Estimated creatinine clearances ranged from 28 to 113 ml/min. Addition of probenecid 500 mg/day to allopurinol therapy decreased plasma urate concentrations by 25%, from mean 0.37 mmol/l (95% CI 0.33-0.41) to mean 0.28 mmol/l (95% CI 0.24-0.32) (p < 0.001); and increased renal urate clearance by 62%, from mean 6.0 ml/min (95% CI 4.5-7.5) to mean 9.6 ml/min (95% CI 6.9-12.3) (p < 0.001). Average steady-state plasma oxypurinol concentrations decreased by 26%, from mean 11.1 mg/l (95% CI 5.0-17.3) to mean 8.2 mg/l (95% CI 4.0-12.4) (p < 0.001); and renal oxypurinol clearance increased by 24%, from mean 12.7 ml/min (95% CI 9.6-15.8) to mean 16.1 ml/min (95% CI 12.0-20.2) (p < 0.05). The additional hypouricemic effect of probenecid 500 mg/day appeared to be lower in patients with renal impairment.. Coadministration of allopurinol with probenecid had a significantly greater hypouricemic effect than allopurinol alone despite an associated reduction of plasma oxypurinol concentrations. Australian Clinical Trials Registry ACTRN012606000276550.

Topics: Allopurinol; Drug Interactions; Drug Therapy, Combination; Gout; Gout Suppressants; Humans; Male; Middle Aged; Oxypurinol; Probenecid; Prospective Studies; Uric Acid; Uricosuric Agents

To compare the efficacy and tolerability of allopurinol 300-600 mg/day versus benzbromarone 100-200 mg/day used to attain a target serum urate concentration (sUr) < or =0.30 mmol/l (5 mg/dl).. A randomised, controlled, open-label, multicentre trial in gout patients with renal function defined as a calculated creatinine clearance > or =50 ml/min. Patients were treated with 300 mg allopurinol or 100 mg benzbromarone once a day (stage 1). If sUr < or =0.30 mmol/l was not attained after 2 months, the dose was doubled to allopurinol 300 mg twice a day or benzbromarone 200 mg once a day (stage 2). The primary end point was treatment success in either of the two stages, defined as clinical tolerability and attainment of biochemical target sUr.. Sixty-five patients were enrolled in stage 1; 36 received allopurinol and 29 received benzbromarone. Fifty-five patients (85%) were analysed at stage 1: the success rates were 8/31 (26%) and 13/25 (52%), respectively, and the difference was -0.26 (95% CI from -0.486 to -0.005), p = 0.049. At stage 2, the success rates were 21/27 (78%) and 18/23 (78%), respectively, and the difference was -0.005 (95% CI from -0.223 to 0.220), p = 1.00. Two patients stopped receiving allopurinol and three stopped receiving benzbromarone because of adverse drug reactions.. Increasing the allopurinol dose from 300 to 600 mg/day and the benzbromarone dose from 100 to 200 mg/day according to the target sUr produced significantly higher success rates (both 78% successful in attaining sUr < or =0.30 mmol/l). No significant differences in treatment success between benzbromarone and allopurinol were found after dose escalation.. ISRCTN49563848).

Topics: Aged; Allopurinol; Benzbromarone; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Gout; Gout Suppressants; Humans; Male; Middle Aged; Oxypurinol; Patient Compliance; Prospective Studies; Treatment Outcome; Uric Acid; Uricosuric Agents

Topics: Adult; Aged; Aged, 80 and over; Alcohol Drinking; Allopurinol; Benzbromarone; Chromatography, Ion Exchange; Drug Therapy, Combination; Gout; Humans; Isoelectric Focusing; Male; Middle Aged; Oxypurinol; Probenecid; Radioimmunoassay; Transferrin

The objectives of this study were to establish if, and to what extent, benzbromarone affects allopurinol/oxypurinol kinetics, and to compare the uric acid lowering capabilities of Allomaron (allopurinol 100 mg plus benzbromarone 20 mg) with the effects of allopurinol alone in patients with confirmed gout. We studied 14 adult men in an open randomized cross-over study. After a 14 day run-in period with Zyloprim (2 x 100 mg allopurinol tablets in the morning), the patients were randomly allocated to morning doses of either Allomaron (2 tablets) or Zyloprim (2 tablets). Seven days later cross-over was effected and the alternative treatment was taken for a further 7 days. On days 7 and 14 the patients came into hospital and venous blood samples were taken over 24 h for allopurinol and oxypurinol assays by HPLC. Serum uric acid was determined on days -14, 1, 7, and 14. Benzbromarone lowered plasma oxypurinol concentrations (Allomaron/Zyloprim mean ratio of AUC0-->24 was 59%; 95% confidence interval 54-64%), but did not affect plasma allopurinol concentrations. Despite this pharmacokinetic interaction of benzbromarone with allopurinol, resulting in lower plasma concentrations of oxypurinol, Allomaron was superior to allopurinol alone in lowering serum uric acid, probably because of the added uricosuric effect of benzbromarone.

Topics: Adult; Aged; Allopurinol; Benzbromarone; Gout; Humans; Male; Middle Aged; Oxypurinol; Uric Acid

Topics: Adult; Aged; Allopurinol; Benzbromarone; Benzofurans; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Gout; Humans; Male; Metabolic Clearance Rate; Middle Aged; Oxypurinol; Purines; Pyrimidines

This study aimed to develop and evaluate an allopurinol adherence tool based on steady-state oxypurinol plasma concentrations, allopurinol's active metabolite.. Plasma oxypurinol concentrations were simulated stochastically from an oxypurinol pharmacokinetic model for allopurinol doses of 100-800 mg daily, accounting for differences in renal function, diuretic use and ethnicity. For each scenario, the 20th percentile for peak and trough concentrations defined the adherence threshold, below which imperfect adherence was assumed. Predictive performance was evaluated using both simulated low adherence and against data from 146 individuals with paired oxypurinol plasma concentrations and adherence measures. Sensitivity and specificity (S&S), negative and positive predictive values (NPV, PPV) and receiver operating characteristic (ROC) area under the curve (AUC) were determined. The predictive performance of the tool was evaluated using adherence data from an external study (CKD-FIX).. The allopurinol adherence tool produced S&S values for trough thresholds of 89-98% and 76-84%, respectively, and 90%-98% and 76-83% for peak thresholds. PPV and NPV were 79-84% and 88-94%, respectively, for trough and 80-85% and 89-98%, respectively, for peak concentrations. The ROC AUC values ranged from 0.84 to 0.88 and from 0.86 to 0.89 for trough and peak concentrations, respectively. S&S values for the external evaluation were found to be 75.8% and 86.5%, respectively, producing an ROC AUC of 0.8113.. A tool to identify people with gout who require additional support to maintain adherence using plasma oxypurinol concentrations was developed and evaluated. The predictive performance of the tool is suitable for adherence screening in clinical trials and may have utility in some clinical practice settings.

Topics: Allopurinol; Gout; Gout Suppressants; Humans; Oxypurinol; Tool Use Behavior

The genetic determinants of the allopurinol dose-concentration relationship have not been extensively studied. We aimed to clarify what factors, including genetic variation in urate transporters, influence oxypurinol pharmacokinetics (PKs). A population PK model for oxypurinol was developed with NONMEM (version 7.3). The influence of urate transporter genetic variants for ABCG2 (rs2231142 and rs10011796), SLC2A9/GLUT9 (rs11942223), SLC17A1/NPT1 (rs1183201), SLC22A12/URAT1 (rs3825018), SLC22A11/OAT4 (rs17300741), and ABCC4/MRP4 (rs4148500), as well as other participant factors on oxypurinol PKs was assessed. Data from 325 people with gout were available. The presence of the T allele for ABCG2 (rs2231142) and SLC17A1/NPT1 (rs1183201) was associated with a 24% and 22% increase in oxypurinol clearance, respectively, in univariate analysis. This effect was not significant in the multivariate analysis. In the final model, oxypurinol PKs were predicted by creatinine clearance, diuretic use, ethnicity, and body weight. We have found that genetic variability in the transporters examined does not appear to influence oxypurinol PKs.

Topics: Allopurinol; Glucose Transport Proteins, Facilitative; Gout; Humans; Organic Anion Transporters; Organic Cation Transport Proteins; Oxypurinol; Uric Acid

The aim of this study was to quantify identifiable sources of variability, including key pharmacogenetic variants in oxypurinol pharmacokinetics and their pharmacodynamic effect on serum urate (SU).. Hmong participants (n = 34) received 100 mg allopurinol twice daily for 7 days followed by 150 mg allopurinol twice daily for 7 days. A sequential population pharmacokinetic pharmacodynamics (PKPD) analysis with non-linear mixed effects modelling was performed. Allopurinol maintenance dose to achieve target SU was simulated based on the final PKPD model.. A one-compartment model with first-order absorption and elimination best described the oxypurinol concentration-time data. Inhibition of SU by oxypurinol was described with a direct inhibitory E. The proposed allopurinol dosing guide uses individuals' fat-free mass, renal function and SLC22A12 rs505802 and PDZK1 rs12129861 genotypes to achieve target SU.

Topics: Adult; Allopurinol; Gout; Gout Suppressants; Humans; Hyperuricemia; Organic Anion Transporters; Organic Cation Transport Proteins; Oxypurinol; Pharmacogenetics

Allopurinol, a first-line gout treatment drug in Australia, was assessed as a wastewater-based epidemiology biomarker of gout via quantification of the urinary metabolite, oxypurinol in wastewater. The in-sewer stability of oxypurinol was examined using laboratory-scale sewer reactors. Wastewater from 75 wastewater treatment plants across Australia, covering approximately 52% (12.2 million) of the country's population, was collected on the 2016 census day. Oxypurinol was quantified in the wastewater samples and population-weighted mass loads calculated. Pearson and Spearman rank-order correlations were applied to investigate any link between allopurinol, other selected wastewater biomarkers, and socio-economic indicators. Oxypurinol was shown to be stable in sewer conditions and suitable as a WBE biomarker. Oxypurinol was detected in all wastewater samples. The estimated consumption of allopurinol ranged from 1.9 to 32 g/day/1000 people equating to 4.8 to 80 DDD/day/1000 people. The prevalence of gout across all tested sewer catchments was between 0.5% to 8%, with a median of 2.9% nationally. No significant positive correlation was observed between allopurinol consumption and alcohol consumption, mean age of catchment population, remoteness or higher socioeconomic status. There was a significant positive correlation with selective analgesic drug use. Wastewater analysis can be used to study gout prevalence and can provide additional insights on population level risk factors when triangulated with other biomarkers.

Topics: Australia; Gout; Oxypurinol; Prevalence; Wastewater

Topics: Allopurinol; Gout; Humans; Oxypurinol

Topics: Allopurinol; ATP Binding Cassette Transporter, Subfamily G, Member 2; Gout; Humans; Neoplasm Proteins; Organic Anion Transporters; Oxypurinol; Xanthine Dehydrogenase

Topics: Adult; Allopurinol; Clinical Trials as Topic; Female; Gout; Gout Suppressants; Humans; Male; Medication Adherence; Middle Aged; Oxypurinol; Uric Acid

Many patients fail to achieve the recommended serum urate (SU) target (<6 mgdl

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; ATP Binding Cassette Transporter, Subfamily G, Member 2; Biomarkers; Female; Gene Frequency; Genotype; Gout; Gout Suppressants; Humans; Logistic Models; Male; Middle Aged; Neoplasm Proteins; Odds Ratio; Oxypurinol; Pharmacogenetics; Pharmacogenomic Variants; Phenotype; Polymorphism, Single Nucleotide; Risk Factors; Treatment Outcome; Uric Acid; Young Adult

The primary aim of this research was to predict the allopurinol maintenance doses required to achieve the target plasma urate of ≤0.36 mmol l(-1) .. A population analysis was conducted in nonmem using oxypurinol and urate plasma concentrations from 133 gout patients. Maintenance dose predictions to achieve the recommended plasma urate target were generated.. The urate response was best described by a direct effects model. Renal function, diuretic use and body size were found to be significant covariates. Dose requirements increased approximately 2-fold over a 3-fold range of total body weight and were 1.25-2 fold higher in those taking diuretics. Renal function had only a modest impact on dose requirements.. Contrary to current guidelines, the model predicted that allopurinol dose requirements were determined primarily by differences in body size and diuretic use. A revised guide to the likely allopurinol doses to achieve the target plasma urate concentration is proposed.

Topics: Allopurinol; Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Gout; Gout Suppressants; Humans; Male; Middle Aged; Models, Biological; Oxypurinol; Predictive Value of Tests; Uric Acid

The aims of this study were to develop a population pharmacokinetic model for allopurinol and oxypurinol and to explore the influence of patient characteristics on allopurinol and oxypurinol pharmacokinetics.. Data from 92 patients with gout and 12 healthy volunteers were available for analysis. A parent-metabolite model with a two-compartment model for allopurinol and a one-compartment model for oxypurinol was fitted to the data using non-linear mixed effects modelling.. Renal function, fat-free mass (FFM) and diuretic use were found to predict differences in the pharmacokinetics of oxypurinol. The population estimates for allopurinol clearance, inter-compartmental clearance, central and peripheral volume were 50, 142 L/h/70 kg FFM, 11.4, 91 L/70 kg FFM, respectively, with a between-subject variability of 33 % (coefficient of variance, CV) for allopurinol clearance. Oxypurinol clearance and volume of distribution were estimated to be 0.78 L/h per 6 L/h creatinine clearance/70 kg FFM and 41 L/70 kg FFM in the final model, with a between-subject variability of 28 and 15 % (CV), respectively.. The pharmacokinetic model provides a means of predicting the allopurinol dose required to achieve target oxypurinol plasma concentrations for patients with different magnitudes of renal function, different body mass and with or without concomitant diuretic use. The model provides a basis for the rational dosing of allopurinol in clinical practice.

Topics: Allopurinol; Body Composition; Cohort Studies; Diuretics; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Female; Gout; Gout Suppressants; Humans; Male; Metabolic Clearance Rate; Models, Biological; Oxypurinol; Xanthine Oxidase

A taste disturbance and anorexia accompanied his other symptoms. How would you proceed?

Topics: Aged, 80 and over; Allopurinol; Dehydration; Diarrhea; Drug Eruptions; Exanthema; Gout; Hawaii; Humans; Male; Oxypurinol; Risk Factors

Oxypurinol, the active metabolite of allopurinol, is the major determinant of the hypouricemic effect of allopurinol. Monitoring oxypurinol concentrations is undertaken to determine adherence to therapy, to investigate reasons for continuing attacks of acute gout and/or insufficiently low plasma urate concentrations despite allopurinol treatment, and to assess the risk of allopurinol hypersensitivity, an adverse effect that has been putatively associated with elevated plasma oxypurinol concentrations.. An audit of request forms requesting plasma oxypurinol concentration measurements received by the pathology service (SydPath) at St Vincent's Hospital, Darlinghurst, Sydney was undertaken for the 7-year period January 2005-December 2011. Patient demographics, biochemical data, including plasma creatinine and uric acid concentrations, comorbidities, and concomitant medications were recorded.. There were 412 requests for determination of an oxypurinol concentration. On 48% of occasions, the time of allopurinol dosing was recorded, while just 79 (19%) blood samples were collected 6-9 hours postdosing, the time window used to establish the therapeutic range for oxypurinol. For these optimally interpretable concentrations, 32 (8%) were within the putative therapeutic range (5-15 mg/L), while 5 (1%) were below and 41 (10%) above this range. The daily dose of allopurinol was documented on only one-third of the request forms. Individually, plasma urate and creatinine concentrations were requested concomitantly with plasma oxypurinol concentrations in 66% and 58% of the cases, respectively; while plasma oxypurinol, urate, and creatinine concentrations were requested concomitantly in 49% of the cases.. Requesting clinicians and blood specimen collectors often fail to provide relevant information (dose, times of last dose, and blood sample collection) to allow the most useful interpretation of oxypurinol concentrations. Concomitant plasma urate and creatinine concentrations should be requested to allow more complete interpretation of the data.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Allopurinol; Child; Child, Preschool; Creatinine; Drug Monitoring; Female; Gout; Gout Suppressants; Humans; Infant; Male; Medication Adherence; Middle Aged; Oxypurinol; Time Factors; Uric Acid; Young Adult

Topics: Adult; Allopurinol; Chromatography, High Pressure Liquid; Drug Overdose; Female; Gout; Gout Suppressants; Humans; Kidney Failure, Chronic; Oxypurinol; Ribonucleosides; Risk Factors; Transsexualism

Our aim was to identify and quantify the sources of variability in oxypurinol pharmacokinetics and explore relationships with plasma urate concentrations.. Non-linear mixed effects modelling was applied to concentration-time data from 155 gouty patients with demographic, medical history and renal transporter genotype information.. A one compartment pharmacokinetic model with first order absorption best described the oxypurinol concentration-time data. Renal function and concomitant medicines (diuretics and probenecid), but not transporter genotype, significantly influenced oxypurinol pharmacokinetics and reduced the between subject variability in the apparent clearance of oxypurinol (CL/F(m)) from 65% to 29%. CL/F(m) for patients with normal, mild, moderate and severe renal impairment was 1.8, 0.6, 0.3 and 0.18 l h(-1), respectively. Model predictions showed a relationship between plasma oxypurinol and urate concentrations and failure to reach target oxypurinol concentrations using suggested allopurinol dosing guidelines.. In conclusion, this first established pharmacokinetic model provides a tool to achieve target oxypurinol plasma concentrations, thereby optimizing the effectiveness and safety of allopurinol therapy in gouty patients with various degrees of renal impairment.

Topics: Adult; Aged; Aged, 80 and over; Diuretics; Drug Interactions; Enzyme Inhibitors; Female; Gout; Gout Suppressants; Humans; Male; Middle Aged; Models, Biological; Nonlinear Dynamics; Oxypurinol; Probenecid; Renal Insufficiency; Severity of Illness Index

The treatment of gout requires a lowering of serum urate (SU) levels, and allopurinol is the drug that is most commonly used for this purpose. The objectives of this study were to define the relationships between allopurinol dose on the one hand and plasma oxypurinol, renal function, and SU levels on the other and to determine the minimum plasma oxypurinol concentration that would result in a target level of <6 mg/dl (0.36 mmol/l) of SU. For this purpose, 82 patients who had been receiving allopurinol for at least 1 month were recruited. Patients with SU <6 mg/dl were followed up quarterly for 12 months. In patients with SU ≥6 mg/dl, the dose of allopurinol was increased to bring the level of SU to <6 mg/dl. These patients were followed up once a month until the SU level remained at <6 mg/dl for 3 consecutive months; thereafter they were seen quarterly. SU, creatinine, and plasma oxypurinol were measured 6-9 hours after administration of the allopurinol dose. There were significant inverse correlations between creatinine clearance (CrCl) and plasma oxypurinol (P = 0.002), between allopurinol dose and SU (P < 0.0001) and between plasma oxypurinol and SU (P < 0.0001). Using receiver operating characteristic analysis, the target SU of <6 mg/dl was achieved in 75% of serum samples with plasma oxypurinol levels of >100 µmol/l (15.2 mg/l). Increasing the allopurinol dose resulted in increased plasma oxypurinol and reduced SU concentrations. Plasma oxypurinol concentrations >100 µmol/l were required to achieve SU <6 mg/dl.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Arthritis, Gouty; Chronic Disease; Creatinine; Dose-Response Relationship, Drug; Drug Monitoring; Enzyme Inhibitors; Female; Gout; Gout Suppressants; Humans; Kidney Function Tests; Male; Middle Aged; Oxypurinol; Standard of Care; Uric Acid

Urate-lowering therapy (ULT), adjusted to achieve and maintain a serum uric acid (SUA) of <6 mg/dl, remains the standard of care for the chronic management of gout. New urate-lowering medications are important options; however, these agents should be reserved for patients who do not tolerate or cannot achieve SUA <6 mg/dl on allopurinol. The result of oxypurinol monitoring to guide allopurinol therapy suggests that allopurinol should still be considered first-line ULT for gout.

Topics: Allopurinol; Arthritis, Gouty; Enzyme Inhibitors; Female; Gout; Gout Suppressants; Humans; Male; Oxypurinol; Uric Acid

Oxypurinol is the active metabolite of allopurinol which is used to treat hyperuricaemia associated with gout. Both oxypurinol and allopurinol inhibit xanthine oxidase which forms uric acid from xanthine and hypoxanthine. Plasma oxypurinol concentrations vary substantially between individuals and the source of this variability remains unclear. The aim of this study was to develop an HPLC-tandem mass spectrometry method to measure oxypurinol in urine to facilitate the study of the renal elimination of oxypurinol in patients with gout. Urine samples (50 microL) were prepared by dilution with a solution of acetonitrile/methanol/water (95/2/3, v/v; 2 mL) that contained the internal standard (8-methylxanthine; 1.5 mg/L), followed by centrifugation. An aliquot (2 microL) was injected. Chromatography was performed on an Atlantis HILIC Silica column (3 microm, 100 mm x 2.1mm, Waters) at 30 degrees C, using a mobile phase comprised of acetonitrile/methanol/50 mM ammonium acetate in 0.2% formic acid (95/2/3, v/v). Using a flow rate of 0.35 mL/min, the analysis time was 6.0 min. Mass spectrometric detection was by selected reactant monitoring (oxypurinol: m/z 150.8-->108.0; internal standard: m/z 164.9-->121.8) in negative electrospray ionization mode. Calibration curves were prepared in drug-free urine across the range 10-200 mg/L and fitted using quadratic regression with a weighting factor of 1/x (r(2) > 0.997, n=7). Quality control samples (20, 80, 150 and 300 mg/L) were used to determine intra-day (n=5) and inter-day (n=7) accuracy and imprecision. The inter-day accuracy and imprecision was 96.1-104% and <11.2%, respectively. Urinary oxypurinol samples were stable when subjected to 3 freeze-thaw cycles and when stored at room temperature for up to 6h. Samples collected from 10 patients, not receiving allopurinol therapy, were screened and showed no significant interferences. The method was suitable for the quantification of oxypurinol in the urine of patients (n=34) participating in a clinical trial to optimize therapy of gout with allopurinol.

Topics: Allopurinol; Chromatography, High Pressure Liquid; Drug Stability; Gout; Humans; Hyperuricemia; Oxypurinol; Regression Analysis; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry; Xanthines

A study was conducted to determine whether combination treatment using allopurinol and benzbromarone was more useful than single allopurinol treatment for the gout and hyperuricemia accompanying renal dysfunction. The subjects were 45 male patients who received urate-lowering treatment and showed a stable serum urate level. The patients were divided into four groups according to the urate-lowering treatment and creatinine clearance (Ccr) (A group: single treatment, normofunction, B group: single treatment, hypofunction, C group: combined treatment, normofunction, D group: combined treatment, hypofunction). There were no differences in serum urate levels among the four groups. Urate clearance (CUA)and daily urinary urate excretion (UUAV) showed significantly high values in the C group, but no difference was seen in the fractional excretion of urate (FEUA) among the four groups. The dosage of allopurinol in the D group was significantly lower than in the A and B groups. Serum oxypurinol concentration in the C group was lower than that in the B group. Oxypurinol clearance (C oxypurinol) in the C group was significantly high compared with the B and D groups. There was a close correlation between C oxypurinol, Ccr, and CUA, with an especially strong correlation between C oxypurinol and CUA. There were no differences in the serum concentration and clearance of xanthine and hypoxanthine among the four groups. Results of the study suggested that combination treatment using allopurinol and benzbromarone for the gout and hyperuricemia accompanying renal dysfunction is more useful, because a lower dose of allopurinol can be used and the serum oxypurinol concentration is reduced compared with single allopurinol treatment.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Benzbromarone; Drug Therapy, Combination; Gout; Gout Suppressants; Humans; Hyperuricemia; Kidney Diseases; Male; Middle Aged; Oxypurinol; Retrospective Studies

Gout is a common and challenging problem in South Auckland, New Zealand. Allopurinol is widely used but urate reduction remains unsatisfactory. Allopurinol dosing guidelines and a therapeutic range for plasma oxypurinol levels have been published.. We aimed to determine the appropriateness of allopurinol dosing according to current guidelines and to assess the relationship between plasma creatinine, oxypurinol and urate. In addition, we assessed the clinical usefulness of the oxypurinol level.. Thirty-one patients, on a stable dose of allopurinol for at least three weeks, had plasma creatinine, urate and oxypurinol measured as part of routine clinical assessment. Relationships between the various methods were examined using regression analysis. Fisher's exact test was used to test associations with categorical variables.. Fifty-five per cent of patients were on higher than recommended doses of allopurinol. There was a statistically significant relationship between calculated creatinine clearance and plasma oxypurinol level. Only 50% of patients with a plasma oxypurinol within the therapeutic range (30-100 micromol/L) had a plasma urate < 0.42 mmol/L and this did not increase significantly in the patients with an oxypurinol level > 100 micromol/L.. There is poor adherence to the current recommended dosing guidelines for allopurinol. Creatinine clearance rather than plasma creatinine needs to be used to predict the dose of allopurinol. The current role of the oxypurinol level is to identify non-compliers with allopurinol therapy. We need further research to clarify whether increasing the dose of allopurinol outside the recommended dose range to reach an oxypurinol level of close to 100 micromol/L may be of benefit in those who have not had sufficient urate reduction.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Creatinine; Drug Evaluation; Female; Gout; Gout Suppressants; Humans; Male; Middle Aged; New Zealand; Oxypurinol; Uric Acid

Not all gout presents with involvement of the big toe, and not all gout patients are middle-aged men. Chronic gout may mimic rheumatoid arthritis; hyperuricemia may develop in postmenopausal women and in organ transplant recipients who are being treated with immunosuppressive agents. Both classic and nonclassic cases may benefit from new therapeutic agents.

Topics: Aged; Algorithms; Allopurinol; Chronic Disease; Diagnosis, Differential; Female; Gout; Gout Suppressants; Humans; Hypertension; Losartan; Male; Middle Aged; Oxypurinol; Urate Oxidase; Virus Diseases

The effect of glucose infusion on renal handling of purine bases and oxypurinol was examined in 6 normal subjects. Five hundred milliliters of 1.1 M glucose solution were administered intravenously in 1 h. Fractional clearances of uric acid, xanthine and oxypurinol were significantly increased during glucose infusion, but that of hypoxanthine was not changed, while a 1-hour infusion of 500 ml of 1.1 M mannitol had no effect on the fractional clearances of purine bases and oxypurinol. These data indicate that the effect of glucose infusion on the renal clearances of uric acid, xanthine and oxypurinol was not related to osmotic diuresis but induced by glycosuria and/or hyperglycemia. Accordingly, the glycosuria- and/or hyperglycemia-induced decrease in the biological half-life of oxypurinol must be considered in the administration of allopurinol to gouty patients with uncontrolled diabetes mellitus.

Topics: Adult; Allopurinol; Biological Transport, Active; Diabetes Complications; Diabetes Mellitus; Glucose; Gout; Half-Life; Humans; Hypoxanthine; Hypoxanthines; Infusions, Intravenous; Kidney; Male; Mannitol; Oxypurinol; Purines; Uric Acid; Xanthine; Xanthines

Topics: Allopurinol; Gout; Humans; Oxypurinol; Pyrimidines; Uricosuric Agents

The application of an electrochemically pre-treated glassy carbon electrode for the amperometric detection of electroactive components, such as tyrosine and oxipurinol, in biological samples was studied in order to demonstrate the usefulness of a pre-anodized electrode in high-performance liquid chromatography. The electrochemical pre-treatment was carried out in 0.2 M phosphate buffer (potassium dihydrogenphosphate-potassium hydroxide, pH 6.5) at 1900 mV vs. Ag/AgCl for 2 min. The pre-anodized electrode response for the oxidation of lactic acid and pyruvic acid was also studied. The electrochemical treatment enhanced and stabilized the electrode response to the oxidation of tyrosine and both acids.

Topics: Chromatography, High Pressure Liquid; Electrodes; Gout; Humans; Lactates; Lactic Acid; Oxypurinol; Phosphates; Pyruvates; Pyruvic Acid; Renal Dialysis; Tyrosine

The plasma concentrations of oxipurinol, the chief metabolite of allopurinol, were studied in 66 patients with gout in whom the dose of allopurinol varied between 100 and 400 mg per day. Renal function ranged from normal to moderately impaired. Plasma oxipurinol concentrations correlated directly with both allopurinol dosage and with renal glomerular function as reflected by the plasma creatinine concentration. Plasma oxipurinol concentrations between 30 and 100 mumol/l were generally effective in controlling hyperuricaemia. However, oxipurinol concentrations usually rose above this range if the daily dose of allopurinol exceeded 300 mg in patients with plasma creatinine concentrations of 0.2 mmol/l or more. In patients with normal renal function, a rise of the plasma xanthine concentration to between 6 and 9 mumol/l suggested a satisfactory degree of xanthine oxidase inhibition. These measurements are particularly useful in patients who are still hyperuricaemic despite the usual doses of allopurinol.

Topics: Allopurinol; Creatine; Gout; Humans; Hypoxanthine; Hypoxanthines; Kidney Function Tests; Oxypurinol; Pyrimidines; Uric Acid; Xanthine; Xanthines

Topics: Aged; Allopurinol; Chronic Disease; Drug Hypersensitivity; Female; Gout; Humans; Oxypurinol; Prognosis

Topics: Acute Kidney Injury; Allopurinol; Chromatography, High Pressure Liquid; Female; Gout; Humans; Hypoxanthine Phosphoribosyltransferase; Kidney Failure, Chronic; Male; Oxypurinol

Twenty male hyperuricaemic patients with normal kidney function were studied and it was found that the serum concentrations and excretions rates in the 24-hour urine of allopurinol and oxipurinol do not differ significantly after 9 days of oral treatment with either 300 mg allopurinol or a combination of 300 mg allopurinol and 60 mg benzbromarone daily. The sum of the excretion rates of the two pyrazolopyrimidines in the 24-hour urine represents 80.9% and 77.1%, respectively of the daily dose of allopurinol given alone or in combination with benzbromarone. As expected, the hypouricaemic effect of the combined therapy turned out to be stronger than that observed after monotherapy with allopurinol, due to the uricosuric component of benzbromarone. The difference was found to be highly significant.

Topics: Adult; Aged; Allopurinol; Benzbromarone; Benzofurans; Creatinine; Drug Therapy, Combination; Glomerular Filtration Rate; Gout; Humans; Male; Middle Aged; Oxypurinol; Pyrimidines; Uric Acid

Topics: Aged; Allopurinol; Arthritis; Drug Hypersensitivity; Female; Gout; Humans; Oxypurinol; Pyrimidines; Uric Acid

The importance of allopurinol drug formulation is discussed regarding the relationship between allopurinol-oxipurinol pharmacokinetics and the mechanism of action. The oxipurinol plasma levels were simulated basing on a single dose regimen and an oxipurinol plasma half life of 14 hours. From these data it is evident, that during long term treatment of hyperuricemia and gout a sustained release allopurinol-formulation fulfills the requirement of adequately maintained oxipurinol plasma levels.

Topics: Allopurinol; Biological Availability; Dose-Response Relationship, Drug; Gout; Half-Life; Humans; Kinetics; Oxypurinol; Uric Acid

A 25-year-old white man with gout and nephropathy and with a previous reaction to allopurinol was given a trial dose of oxypurinol. He developed malaise, a generalized erythematous reaction with edema, pruritus, and emesis; this was clinically identical to the reaction he experienced with allopurinol. When the patient's lymphocytes were exposed in vitro to oxypurinol and allopurinol, increased DNA synthesis was observed, suggesting an immunologic basis for the reaction. This patient indicates that clinical cross reactivity to allopurinol and oxypurinol does occur and may be of an immunologic basis. There is a need for additional xanthine oxidase inhibitors for such patients.

Topics: Adult; Allopurinol; Cross Reactions; Drug Eruptions; Drug Hypersensitivity; Gout; Humans; Lymphocyte Activation; Male; Oxypurinol; Pyrimidines; Skin Tests

Oxithiopurinol, [4-thio-6-hydroxypyrazolo(3,4-d)pyrimidine] has been caracterized in urines of patients treated with Thiopurinol : the principle involved is the precipitation of both oxithiopurinol and uric acid in combination with cupric hydroxide. The urinary oxithopurinol content is determined by means of anion and cation exchange resins. 56 to 70 per cent of the daily dose of Thiopurinol are eliminated in urine as oxithiopurinol.

Topics: Allopurinol; Biotransformation; Chromatography, Ion Exchange; Chromatography, Thin Layer; Gout; Humans; Hydroxylation; Oxypurinol; Pyrimidines; Sulfhydryl Compounds

Topics: Allopurinol; Gout; Humans; Oxypurinol; Probenecid; Sulfinpyrazone; Uric Acid; Uricosuric Agents