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1.
Drug Test Anal ; 14(8): 1519-1524, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35355431

RESUMO

The increasing global prevalence of gout and diabetes has led to a rise in the use of their respective medications, allopurinol and metformin. These are excreted via urine as oxypurinol and metformin and are discharged into wastewater and the environment. Current environmental monitoring of those two polar chemicals requires labour intensive and potentially inefficient sample pre-treatments, such as using solid-phase extraction or freeze-drying. This study validated a sensitive and simple method using direct-injection LC-MS/MS for the simultaneous measurement of oxypurinol and metformin in wastewater. The final method utilised a hydrophilic interaction liquid chromatography together with simple filtration through 0.2 µm regenerated cellulose filter followed by dilution in acetonitrile with a dilution factor of 10. The developed method was validated with the limit of quantifications (LOQ) of 0.11 and 0.34 µg/L for metformin and oxypurinol, respectively. The new method was applied to 42 influent wastewater samples and 6 effluent samples collected from 6 Australian wastewater treatment plants. Both compounds were detected well above the LOQ at concentrations 29-214 µg/L in influent and 2-53 µg/L in effluent for metformin, and 24-248 µg/L in influent and 4-81 µg/L in effluent for oxypurinol, demonstrating its high applicability.


Assuntos
Metformina , Poluentes Químicos da Água , Austrália , Cromatografia Líquida/métodos , Interações Hidrofóbicas e Hidrofílicas , Oxipurinol/análise , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos , Águas Residuárias/análise , Poluentes Químicos da Água/análise
2.
Int J Mol Sci ; 23(3)2022 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-35163565

RESUMO

Peroxisome proliferator-activated receptor delta (PPARD) is a nuclear receptor known to play an essential role in regulation of cell metabolism, cell proliferation, inflammation, and tumorigenesis in normal and cancer cells. Recently, we found that a newly generated villin-PPARD mouse model, in which PPARD is overexpressed in villin-positive gastric progenitor cells, demonstrated spontaneous development of large, invasive gastric tumors as the mice aged. However, the role of PPARD in regulation of downstream metabolism in normal gastric and tumor cells is elusive. The aim of the present study was to find PPARD-regulated downstream metabolic changes and to determine the potential significance of those changes to gastric tumorigenesis in mice. Hyperpolarized [1-13C] pyruvate magnetic resonance spectroscopy, nuclear magnetic resonance spectroscopy, and liquid chromatography-mass spectrometry were employed for metabolic profiling to determine the PPARD-regulated metabolite changes in PPARD mice at different ages during the development of gastric cancer, and the changes were compared to corresponding wild-type mice. Nuclear magnetic resonance spectroscopy-based metabolomic screening results showed higher levels of inosine monophosphate (p = 0.0054), uracil (p = 0.0205), phenylalanine (p = 0.017), glycine (p = 0.014), and isocitrate (p = 0.029) and lower levels of inosine (p = 0.0188) in 55-week-old PPARD mice than in 55-week-old wild-type mice. As the PPARD mice aged from 10 weeks to 35 weeks and 55 weeks, we observed significant changes in levels of the metabolites inosine monophosphate (p = 0.0054), adenosine monophosphate (p = 0.009), UDP-glucose (p = 0.0006), and oxypurinol (p = 0.039). Hyperpolarized [1-13C] pyruvate magnetic resonance spectroscopy performed to measure lactate flux in live 10-week-old PPARD mice with no gastric tumors and 35-week-old PPARD mice with gastric tumors did not reveal a significant difference in the ratio of lactate to total pyruvate plus lactate, indicating that this PPARD-induced spontaneous gastric tumor development does not require glycolysis as the main source of fuel for tumorigenesis. Liquid chromatography-mass spectrometry-based measurement of fatty acid levels showed lower linoleic acid, palmitic acid, oleic acid, and steric acid levels in 55-week-old PPARD mice than in 10-week-old PPARD mice, supporting fatty acid oxidation as a bioenergy source for PPARD-expressing gastric tumors.


Assuntos
Metabolômica/métodos , Proteínas dos Microfilamentos/genética , PPAR delta/genética , Neoplasias Gástricas/patologia , Regulação para Cima , Monofosfato de Adenosina/análise , Animais , Cromatografia Líquida , Ácidos Graxos/análise , Feminino , Engenharia Genética , Imageamento por Ressonância Magnética , Masculino , Espectrometria de Massas , Camundongos , Neoplasias Experimentais , Oxipurinol/análise , Regiões Promotoras Genéticas , Estudos Prospectivos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Uridina Difosfato Glucose/análise
3.
Clin Pharmacokinet ; 61(2): 321-333, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34617261

RESUMO

BACKGROUND: Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates. OBJECTIVE: The aim of the current study was to establish the pharmacokinetics (PK) of allopurinol and oxypurinol, and the pharmacodynamics (PD) of both compounds on hypoxanthine, xanthine, and uric acid in HIE neonates. The dosage used and the effect of allopurinol in this population, either or not undergoing therapeutic hypothermia (TH), were evaluated. METHODS: Forty-six neonates from the ALBINO study and two historical clinical studies were included. All doses were administered on the first day of life. In the ALBINO study (n = 20), neonates received a first dose of allopurinol 20 mg/kg, and, in the case of TH (n = 13), a second dose of allopurinol 10 mg/kg. In the historical cohorts (n = 26), neonates (all without TH) received two doses of allopurinol 20 mg/kg in total. Allopurinol and oxypurinol population PK, and their effects on inhibiting conversions of hypoxanthine and xanthine to uric acid, were assessed using nonlinear mixed-effects modelling. RESULTS: Allopurinol and oxypurinol PK were described by two sequential one-compartment models with an autoinhibition effect on allopurinol metabolism by oxypurinol. For allopurinol, clearance (CL) was 0.83 L/h (95% confidence interval [CI] 0.62-1.09) and volume of distribution (Vd) was 2.43 L (95% CI 2.25-2.63). For metabolite oxypurinol, CL and Vd relative to a formation fraction (fm) were 0.26 L/h (95% CI 0.23-0.3) and 11 L (95% CI 9.9-12.2), respectively. No difference in allopurinol and oxypurinol CL was found between TH and non-TH patients. The effect of allopurinol and oxypurinol on XO inhibition was described by a turnover model of hypoxanthine with sequential metabolites xanthine and uric acid. The combined allopurinol and oxypurinol concentration at the half-maximal XO inhibition was 0.36 mg/L (95% CI 0.31-0.42). CONCLUSION: The PK and PD of allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid in neonates with HIE were described. The dosing regimen applied in the ALBINO trial leads to the targeted XO inhibition in neonates treated with or without TH.


Assuntos
Hipóxia-Isquemia Encefálica , Oxipurinol , Alopurinol/farmacologia , Alopurinol/uso terapêutico , Biomarcadores , Inibidores Enzimáticos , Humanos , Hipoxantina , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Recém-Nascido , Oxipurinol/farmacocinética , Ácido Úrico , Xantina , Xantina Oxidase
4.
Clin Transl Sci ; 14(4): 1431-1443, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33931953

RESUMO

The missense variant, breast cancer resistance protein (BCRP) p.Q141K, which encodes a reduced function BCRP, has been linked to poor response to allopurinol. Using a multifaceted approach, we aimed to characterize the relationship(s) between BCRP p.Q141K, the pharmacokinetics (PK) and pharmacodynamics (PD) of oxypurinol (the active metabolite of allopurinol), and serum uric acid (SUA) levels. A prospective clinical study (NCT02956278) was conducted in which healthy volunteers were given a single oral dose of 300 mg allopurinol followed by intensive blood sampling. Data were analyzed using noncompartmental analysis and population PK/PD modeling. Additionally, electronic health records were analyzed to investigate whether clinical inhibitors of BCRP phenocopied the effects of the p.Q141K variant with respect to SUA. Subjects homozygous for p.Q141K had a longer half-life (34.2 ± 12.2 h vs. 19.1 ± 1.42 h) of oxypurinol. The PK/PD model showed that women had a 24.8% lower volume of distribution. Baseline SUA was affected by p.Q141K genotype and renal function; that is, it changed by 48.8% for every 1 mg/dl difference in serum creatinine. Real-world data analyses showed that patients prescribed clinical inhibitors of BCRP have higher SUA levels than those that have not been prescribed inhibitors of BCRP, consistent with the idea that BCRP inhibitors phenocopy the effects of p.Q141K on uric acid levels. This study identified important covariates of oxypurinol PK/PD that could affect its efficacy for the treatment of gout as well as a potential side effect of BCRP inhibitors on increasing uric acid levels, which has not been described previously.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Proteínas de Neoplasias/genética , Oxipurinol/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Creatinina/sangue , Creatinina/metabolismo , Feminino , Taxa de Filtração Glomerular , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Mutação de Sentido Incorreto , Proteínas de Neoplasias/metabolismo , Oxipurinol/administração & dosagem , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Eliminação Renal , Fatores Sexuais , Ácido Úrico/sangue , Ácido Úrico/metabolismo , Adulto Jovem
5.
Curr Pharm Des ; 26(35): 4515-4521, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32787748

RESUMO

BACKGROUND: COVID-19, caused by SARS-CoV-2, is a potentially lethal, rapidly-expanding pandemic and many efforts are being carried out worldwide to understand and control the disease. COVID-19 patients may display a cytokine release syndrome, which causes severe lung inflammation, leading, in many instances, to death. OBJECTIVE: This paper is intended to explore the possibilities of controlling the COVID-19-associated hyperinflammation by using licensed drugs with anti-inflammatory effects. HYPOTHESIS: We have previously described that pentoxifylline alone, or in combination with oxypurinol, reduces the systemic inflammation caused by experimentally-induced pancreatitis in rats. Pentoxifylline is an inhibitor of TNF-α production and oxypurinol inhibits xanthine oxidase. TNF-α, in turn, activates other inflammatory genes such as Nos2, Icam or IL-6, which regulate migration and infiltration of neutrophils into the pulmonary interstitial tissue, causing injury to the lung parenchyma. In acute pancreatitis, the anti-inflammatory action of pentoxifylline seems to be mediated by the prevention of the rapid and presumably transient loss of PP2A activity. This may also occur in the hyperinflammatory -cytokine releasing phase- of SARS-CoV-2 infection. Therefore, it may be hypothesized that early treatment of COVID-19 patients with pentoxifylline, alone or in combination with oxypurinol, would prevent the potentially lethal acute respiratory distress syndrome. CONCLUSION: Pentoxifylline and oxypurinol are licensed drugs used for diseases other than COVID-19 and, therefore, phase I clinical trials would not be necessary for the administration to SARS-CoV-2- infected people. It would be worth investigating their potential effects against the hyperinflammatory response to SARS-CoV-2 infection.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/prevenção & controle , Oxipurinol/uso terapêutico , Pentoxifilina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Doença Aguda , Animais , Betacoronavirus , COVID-19 , Síndrome da Liberação de Citocina/virologia , Humanos , Pancreatite , Pandemias , Ratos , SARS-CoV-2
6.
Best Pract Res Clin Rheumatol ; 34(4): 101501, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32265121

RESUMO

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.


Assuntos
Alopurinol/efeitos adversos , Hipersensibilidade a Drogas , Gota , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/prevenção & controle , Gota/tratamento farmacológico , Supressores da Gota/efeitos adversos , Humanos , Oxipurinol/uso terapêutico
7.
J Pharm Biomed Anal ; 185: 113204, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32126445

RESUMO

Allopurinol is the most commonly used drug for the treatment of hyperuricemia in people, and in view of the risks of fatal hypersensitivity in patients with renal dysfunction, doses based on the glomerular filtration rate are proposed. In veterinary medicine, allopurinol is used in the treatment of canine leishmaniasis (CanL) caused by Leishmania infantum owing to the drug action of inhibiting the parasite's RNA synthesis. However, renal dysfunction frequently ensues from disease progression in dogs. The purpose of the present study was to standardize and validate a sensitive high-performance liquid chromatography-mass spectrometric (HPLC-MS/MS) method to determine the concentration of allopurinol and its active metabolite oxypurinol in canine urine for clinical pharmacokinetic investigation. Urine samples of eleven (11) dogs with naturally occurring CanL and in the maintenance phase of the treatment with alopurinol were used. For the chromatographic analysis of urine, the mobile phase consisted of a solution of 0.1 % formic acid (88 %) in 10 mM ammonium acetate. Separation of allopurinol and oxypurinol occurred in a flow of 0.8 mL/min on a C8 reverse phase column 5 µm, and acyclovir was the internal standard. The HPLC-MS/MS method was validated by reaching the limits of detection and quantification, reproducibility and linearity. The lower limit of quantification achieved by the method was 10 µg/mL for both allopurinol and oxypurinol. Calibration curves were prepared in blank urine added with allopurinol at concentrations of 10-1000 µg/mL, and oxypurinol at 10-200 µg/mL. Coefficients of variation of less than 15 % between intracurrent and intercurrent accuracy values were observed for both allopurinol and oxypurinol. Urine test samples remained stable after being subjected to freeze-thaw cycles and remaining at room temperature for 4 h. The method proved to be adequate to quantify allopurinol and oxypurinol in urine samples from dogs under treatment.


Assuntos
Alopurinol/urina , Cães/urina , Monitoramento de Medicamentos/veterinária , Leishmaniose/veterinária , Oxipurinol/urina , Administração Oral , Alopurinol/administração & dosagem , Alopurinol/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão/métodos , Cães/parasitologia , Monitoramento de Medicamentos/métodos , Leishmania infantum/isolamento & purificação , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Limite de Detecção , Masculino , Oxipurinol/farmacocinética , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
8.
Angiology ; 71(4): 315-323, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32000517

RESUMO

Several trials have been completed in patients with heart failure (HF) treated with uric acid (UA)-lowering agents with inconsistent results. We aimed to investigate whether lowering UA would have an effect on mortality and cardiovascular (CV) events in patients with HF in a systematic review and meta-analysis. The primary outcome measures were all-cause mortality, CV mortality, CV events, and CV hospitalization in patients with HF. We included 11 studies in our final analysis. Overall, allopurinol treatment was associated with a significant increase in the risk for all-cause mortality (hazard ratio [HR]: 1.24, 95% confidence interval [CI]: 1.04-1.49, P = .02). The trial heterogeneity is high (heterogeneity χ2 = 37.3, I2 = 73%, P < .001). With regard to CV mortality, allopurinol treatment was associated with a 42% increased risk of CV mortality (HR: 1.42, 95% CI: 1.11-1.81, P = .005). There was a trend toward increased CV hospitalization in the same group (HR: 1.21, 95% CI: 0.95-1.53, P = .12). Uric acid-lowering treatments increase all-cause and CV mortality but did not increase CV hospitalization significantly in this study.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Xantina Oxidase/antagonistas & inibidores , Alopurinol/uso terapêutico , Febuxostat/uso terapêutico , Insuficiência Cardíaca/mortalidade , Humanos , Oxipurinol/uso terapêutico , Ácido Úrico
9.
Sci Total Environ ; 715: 136925, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32007890

RESUMO

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.


Assuntos
Gota , Austrália , Oxipurinol , Prevalência , Águas Residuárias
10.
Clin Transl Sci ; 13(1): 110-115, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31444839

RESUMO

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).


Assuntos
Alopurinol/administração & dosagem , Supressores da Gota/administração & dosagem , Gota/tratamento farmacológico , Oxipurinol/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Idoso , Alopurinol/farmacocinética , Índice de Massa Corporal , Creatinina/sangue , Creatinina/metabolismo , Relação Dose-Resposta a Droga , Feminino , Gota/sangue , Gota/diagnóstico , Gota/genética , Supressores da Gota/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Oxipurinol/metabolismo , Curva ROC , Eliminação Renal , Resultado do Tratamento , Ácido Úrico/sangue
11.
Drug Metab Lett ; 13(2): 111-122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31613735

RESUMO

BACKGROUND: Clinical development of lesinurad, a selective uric acid reabsorption inhibitor, required analysis of lesinurad in plasma from special patient populations. METHODS: EMA and FDA bioanalytical method validation guidance have recommended studying matrix effects on quantitation if samples from special patient populations are to be analyzed. In addition to lesinurad (plasma protein binding 98.2%), the matrix effects from special population plasma on the quantitation of verapamil (PPB 89.6%), allopurinol and oxypurinol (PPB negligible) were also investigated. RESULTS: The plasma from special population patients had no matrix effects on the three quantification methods with stable isotope labeled internal standard, protein precipitation extraction, and LC-MS/MS detection. The validated lesinurad plasma quantification method was successfully applied for the pharmacokinetic evaluations to support the clinical studies in renal impaired patients. CONCLUSION: Special population plasma did not affect quantitation of drugs with a wide range of plasma protein binding levels in human plasma. With the confirmation that there is no impact on quantification from the matrix, the bioanalytical method can be used to support the pharmacokinetic evaluations for clinical studies in special populations.


Assuntos
Insuficiência Hepática/metabolismo , Insuficiência Renal/metabolismo , Tioglicolatos/sangue , Triazóis/sangue , Uricosúricos/sangue , Alopurinol/farmacocinética , Calibragem , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida de Alta Pressão/normas , Ensaios Clínicos como Assunto , Insuficiência Hepática/sangue , Insuficiência Hepática/fisiopatologia , Humanos , Rim/metabolismo , Rim/fisiopatologia , Fígado/metabolismo , Fígado/fisiopatologia , Oxipurinol/sangue , Oxipurinol/farmacocinética , Padrões de Referência , Insuficiência Renal/sangue , Insuficiência Renal/fisiopatologia , Reabsorção Renal , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Espectrometria de Massas em Tandem/normas , Tioglicolatos/farmacocinética , Triazóis/farmacocinética , Uricosúricos/farmacocinética , Verapamil/sangue , Verapamil/farmacocinética
12.
PLoS One ; 14(3): e0213786, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30870504

RESUMO

A fixed dose combination of lesinurad and allopurinol has been recently approved by USFDA and EMA for treatment of gout-associated hyperuricemia in patients who have not achieved target serum uric acid levels with allopurinol alone. In this study, an ultra-performance hydrophilic interaction liquid chromatography (UPHILIC) coupled with tandem mass spectrometry method was developed and validated for simultaneous determination of allopurinol, oxypurinol and lesinurad in rat plasma. Liquid liquid extraction using ethyl acetate as extracting agent was used for samples extraction procedure. Acquity UPLC HILIC column (100 mm x 2.1, 1.7µm) was used for separation of allopurinol, oxypurinol, lesinurad and internal standard (5-Florouracil). The mobile phase consisting of acetonitrile, water and formic acid (95:5:0.1, v/v/v), were eluted at 0.3 mL/min flow rate having total chromatographic run time of 3 min per sample. The analytes were detected on Acquity triple quadrupole mass spectrometer equipped with a Z-Spray electrospray ionization (ESI). The ESI source was operated in negative mode and multiple reaction monitoring was used for ion transition for all compounds. The precursor to product ion transition of m/z 134.94 > 64.07 for allopurinol, 150.89 > 41.91 for oxypurinol, 401.90 > 176.79 for lesinurad and 128.85 >41.92 for internal standard were used for identification and quantification. The calibration curves for all analytes were found to be linear with weighing factor of 1/x2 using regression analysis. The developed assay was successfully applied in an oral pharmacokinetic study of allopurinol, oxypurinol and lesinurad in rats.


Assuntos
Alopurinol/farmacocinética , Cromatografia Líquida/métodos , Interações Hidrofóbicas e Hidrofílicas , Oxipurinol/farmacocinética , Espectrometria de Massas em Tandem/métodos , Tioglicolatos/farmacocinética , Triazóis/farmacocinética , Alopurinol/sangue , Animais , Oxipurinol/sangue , Ratos , Reprodutibilidade dos Testes , Tioglicolatos/sangue , Distribuição Tecidual , Triazóis/sangue
13.
Drug Metab Pharmacokinet ; 34(2): 155-158, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30826184

RESUMO

The inhibitor of uric acid reabsorptive transporter URAT1 in kidney is drawing attention as a drug target for hyperuricemia. However, it is difficult to evaluate efficacy of URAT1 inhibitors in vivo using laboratory animals due to species difference in uric acid metabolism. In the present study, the usefulness of exogenously administering uric acid analogues resistant to uricase was investigated for in vivo evaluation of transport activity of rUrat1 in rats. Uptake of examined four uric acid analogues by rUrat1-expressing Xenopus oocytes was significantly higher than that by water-injected oocytes. In metabolism studies, disappearance of these compounds was negligible, while uric acid was significantly decreased. When oxypurinol was administered to rats, fractional excretion (FE) was 0.4, suggesting reabsorption of oxypurinol. Moreover, FE of oxypurinol was tended to be increased, but not statistically different, by co-administration of a uricosuric agent FYU-981, while plasma concentration of oxypurinol was not affected. These results suggested that oxypurinol is a potential uric acid analogue, although it was not suitable as a probe of uric acid in in vivo study. Our findings may contribute to discovery and development of novel uricosuric agent targeting URAT1.


Assuntos
Proteínas de Transporte de Ânions/metabolismo , Oxipurinol/análise , Ácido Úrico/análogos & derivados , Ácido Úrico/análise , Xenobióticos/análise , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Masculino , Oxipurinol/administração & dosagem , Oxipurinol/metabolismo , Ratos , Ratos Wistar , Ácido Úrico/metabolismo , Xenobióticos/metabolismo
14.
Clin Pharmacol Ther ; 106(3): 623-631, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30924126

RESUMO

Allopurinol, which lowers uric acid (UA) concentration, is increasingly being recognized for its benefits in cardiovascular and renal disease. However, response to allopurinol is variable. We gathered samples from 4,446 multiethnic subjects for a genome-wide association study of allopurinol response. Consistent with previous studies, we observed that the Q141K variant in ABCG2 (rs2231142), which encodes the efflux pump breast cancer resistance protein (BCRP), associated with worse response to allopurinol. However, for the first time this association reached genome-wide level significance (P = 8.06 × 10-11 ). Additionally, we identified a novel association with a variant in GREM2 (rs1934341, P = 3.22 × 10-6 ). In vitro studies identified oxypurinol, the active metabolite of allopurinol, as an inhibitor of the UA transporter GLUT9, suggesting that oxypurinol may modulate UA reabsorption. These results provide strong evidence for a role of BCRP Q141K in allopurinol response, and suggest that allopurinol may have additional hypouricemic effects beyond xanthine oxidase inhibition.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Alopurinol/farmacologia , Proteínas de Neoplasias/genética , Ácido Úrico/metabolismo , Idoso , Idoso de 80 Anos ou mais , Citocinas/genética , Feminino , Estudo de Associação Genômica Ampla , Proteínas Facilitadoras de Transporte de Glucose/antagonistas & inibidores , Humanos , Masculino , Pessoa de Meia-Idade , Oxipurinol/farmacologia , Prognóstico
15.
Drug Metab Pharmacokinet ; 34(1): 111-112, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30709683
16.
Free Radic Biol Med ; 129: 364-371, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30312761

RESUMO

Generation of superoxide by xanthine oxidase can be stimulated under ischemic and aberrant calcium homeostasis. Because patients and mice with Duchenne muscular dystrophy (DMD) suffer from ischemia and excessive calcium influx, we tested the hypothesis that xanthine oxidase activity is elevated and contributes to disease pathology. Xanthine oxidase activity was measured by urinary isoxanthopterin in DMD patients at rest and in response to exercise. Urinary isoxanthopterin/creatinine was elevated compared to age-matched controls and Becker muscular dystrophy (BMD) patients. Concentrations were also increased after a six minute walk test in ambulatory patients. We also measured urinary isoxanthopterin in wildtype mice and a number of dystrophic mouse models; the DMD mouse model (mdx), mdx mice overexpressing a variety of transgenic miniaturized and chimeric skeletal muscle-specific dystrophins and utrophin and the ß-sarcoglycan deficient (Scgb-/-) mouse which represents type 2E human limb-girdle muscular dystrophy. Mdx and Scgb-/-mice had greater urinary isoxanthopterin/creatinine than wildtype mice while mdx mice expressing dystrophin or utrophin linking the extracellular matrix to the actin cytoskeleton were not different than wildtype. We also measured higher levels of urinary ortho-tyrosine in humans and mice deficient for dystrophin to confirm elevated oxidative stress. Surprisingly, mdx had lower xanthine oxidase protein levels and higher mRNA in gastrocnemius muscle compared to wildtype mice, however, the enzymatic activity of skeletal muscle xanthine oxidase was elevated above wildtype and a transgenic rescued mdx mouse (DysΔMTB-mdx). Downhill treadmill running also caused significant increases in mdx urinary isoxanthopterin that was prevented with the xanthine oxidase inhibitor allopurinol. Similarly, in vitro eccentric contraction-induced force drop of mdx muscle was attenuated by the allopurinol metabolite, oxypurinol. Together, our data suggests hyper-activity of xanthine oxidase in DMD, identifies xanthine oxidase activity as a contributing factor in eccentric contraction-induced force drop of dystrophin-deficient skeletal muscle and highlights the potential of isoxanthopterin as a noninvasive biomarker in DMD.


Assuntos
Distrofina/deficiência , Distrofia Muscular Animal/enzimologia , Distrofia Muscular de Duchenne/enzimologia , Xantina Oxidase/urina , Xantopterina/urina , Adolescente , Alopurinol/farmacologia , Animais , Biomarcadores/urina , Estudos de Casos e Controles , Creatinina/urina , Distrofina/genética , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos mdx , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/enzimologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular Animal/tratamento farmacológico , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/fisiopatologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/fisiopatologia , Oxipurinol/farmacologia , Sarcoglicanas/deficiência , Sarcoglicanas/genética , Tirosina/urina , Utrofina/deficiência , Utrofina/genética , Xantina Oxidase/genética , Adulto Jovem
18.
J Clin Pharmacol ; 58(9): 1214-1222, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29733447

RESUMO

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 (Cmax ) for allopurinol by 33%; the area under the plasma concentration-time curve (AUC) was unaffected. Oxypurinol Cmax and AUC were reduced 32% and 38%, respectively, by verinurad. Colchicine plasma exposure was unaltered by verinurad. The maximum decrease in serum urate was greater with verinurad + allopurinol (65%) than with verinurad (51%) or allopurinol (43%) alone. Compared with the baseline rate, the maximum rate of uric acid excreted in urine was +56% with verinurad, -46% with allopurinol, and unchanged with verinurad + allopurinol. No serious AEs, discontinuations due to AEs, or clinically significant laboratory abnormalities were noted. Despite decreased systemic exposure of allopurinol and oxypurinol in the presence of verinurad, the combination resulted in greater serum urate reduction compared with either drug alone and was well tolerated at the studied doses.


Assuntos
Supressores da Gota/farmacocinética , Supressores da Gota/uso terapêutico , Gota/tratamento farmacológico , Naftalenos/farmacocinética , Naftalenos/uso terapêutico , Propionatos/farmacocinética , Propionatos/uso terapêutico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Adolescente , Adulto , Idoso , Alopurinol/metabolismo , Alopurinol/farmacocinética , Alopurinol/uso terapêutico , Área Sob a Curva , Esquema de Medicação , Supressores da Gota/administração & dosagem , Supressores da Gota/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Naftalenos/administração & dosagem , Naftalenos/efeitos adversos , Oxipurinol/metabolismo , Oxipurinol/farmacocinética , Propionatos/administração & dosagem , Propionatos/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Ácido Úrico/sangue , Adulto Jovem
19.
Chem Res Toxicol ; 31(3): 165-167, 2018 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-29436218

RESUMO

It is unclear whether priming of naïve T cells to drugs is detectable in healthy human donors expressing different human leukocyte antigen (HLA) alleles. Thus, we examined T cell priming with drugs associated with HLA risk alleles and control compounds in 14 HLA-typed donors. Nitroso sulfamethoxazole and piperacillin activated T cells from all donors, whereas responses to carbamazepine and oxypurinol were only seen in donors expressing HLA-B*15:02 and HLA-B*58:01, respectively. Weak flucloxacillin-specific T cell responses were detected in donors expressing HLA-B*57:01 and HLA-B*58:01. These data show that the priming of T cells with certain drugs is skewed toward donors expressing specific HLA alleles.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Antígenos HLA/imunologia , Ativação Linfocitária/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/imunologia , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/imunologia , Carbamazepina/efeitos adversos , Carbamazepina/imunologia , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/imunologia , Antígenos HLA-B/imunologia , Humanos , Compostos Nitrosos/efeitos adversos , Compostos Nitrosos/imunologia , Oxipurinol/efeitos adversos , Oxipurinol/imunologia , Piperacilina/efeitos adversos , Piperacilina/imunologia , Sulfametoxazol/efeitos adversos , Sulfametoxazol/imunologia , Linfócitos T/imunologia
20.
Drug Metab Pharmacokinet ; 33(1): 77-81, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29342419

RESUMO

Hyperuricemia induces gout and kidney stones and accelerates the progression of renal and cardiovascular diseases. Adenosine 5'-triphosphate-binding cassette subfamily G member 2 (ABCG2) is a urate transporter, and common dysfunctional variants of ABCG2, non-functional Q126X (rs72552713) and semi-functional Q141K (rs2231142), are risk factors for hyperuricemia and gout. A recent genome wide association study suggested that allopurinol, a serum uric acid-lowering drug that inhibits xanthine dehydrogenase, is a potent substrate of ABCG2. In this study, we aimed to examine the transport of xanthine dehydrogenase inhibitors via ABCG2. Our results show that ABCG2 transports oxypurinol, an active metabolite of allopurinol, whereas allopurinol and febuxostat, a new xanthine dehydrogenase inhibitor, are not substrates of ABCG2. The amount of oxypurinol transported by ABCG2 vesicles significantly increased in the presence of ATP, compared to that observed with mock vesicles. Since the half-life of oxypurinol is longer than that of allopurinol, the xanthine dehydrogenase-inhibiting effect of allopurinol mainly depends on its metabolite, oxypurinol. Our results indicate that the serum level of oxypurinol would increase in patients with ABCG2 dysfunction.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Alopurinol/metabolismo , Proteínas de Neoplasias/metabolismo , Oxipurinol/metabolismo , Xantina Desidrogenase/antagonistas & inibidores , Xantina Desidrogenase/metabolismo , Transporte Biológico/fisiologia , Membrana Celular/metabolismo , Inibidores Enzimáticos/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Hiperuricemia/metabolismo
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