The Experts below are selected from a list of 264 Experts worldwide ranked by ideXlab platform
Tetsuya Yamamoto - One of the best experts on this subject based on the ideXlab platform.
-
Effects of bovine milk ingestion on urinary excretion of Oxypurinol and uric acid.
International journal of clinical pharmacology and therapeutics, 2011Co-Authors: Masafumi Kurajoh, Yuji Moriwaki, Zenta Tsutsumi, Chihiro Okuda, Asako Yamamoto, Hidenori Koyama, Tetsuya YamamotoAbstract:Objective Although allopurinol is a xanthine oxidase inhibitor, its overall effect may be due to the action of Oxypurinol, a metabolite of allopurinol and another xanthine oxidase inhibitor, since the biological half-life of Oxypurinol is longer than that of allopurinol. Oxypurinol shares a renal transport pathway with uric acid and ingestion of bovine milk increases the urinary excretion of uric acid. Therefore, we investigated whether its ingestion promotes the urinary excretion of Oxypurinol. Subjects/methods Bovine milk (15 ml/kg body weight) was administered to 6 healthy subjects who took allopurinol (300 mg) 12 h prior to ingestion. In addition, a control experiment was performed with the same subjects using the same protocol, except for the ingestion of water instead of bovine milk. Blood and urine samples were collected before and after bovine and water ingestion. Results In the bovine milk ingestion experiment, the urinary excretion values of Oxypurinol and uric acid were increased by 18% and 38%, respectively, and the fractional excretion values of Oxypurinol and uric acid were increased by 20% and 40%, respectively, whereas those did not change in the control experiment. In addition, the concentration of alanine and sum of concentrations of amino acids were increased by 16% and 20%, respectively, in the bovine milk ingestion experiment. Conclusion These results suggest that bovine milk ingestion promotes the urinary excretion of Oxypurinol as well as uric acid by increasing amino acid concentration.
-
Plasma concentrations and urinary excretion of purine bases (uric acid, hypoxanthine, and xanthine) and Oxypurinol after rigorous exercise.
Metabolism: clinical and experimental, 2006Co-Authors: Mitsuharu Kaya, Yuji Moriwaki, Sumio Takahashi, Zenta Tsutsumi, Asako Yamamoto, Taku Inokuchi, Junzou Tsuzita, Yoshitaka Oku, Tetsuya YamamotoAbstract:Abstract To investigate the effects of exercise on the plasma concentrations and urinary excretion of purine bases and Oxypurinol, we performed 3 experiments with 6 healthy male subjects. The first was a combination of allopurinol intake (300 mg) and exercise (V˙ o 2max, 70%) (combination experiment), the second was exercise alone (exercise-alone experiment), and the third was allopurinol intake alone (allopurinol-alone experiment). In the combination experiment, exercise increased the concentrations of purine bases and noradrenaline in plasma, as well as lactic acid in blood and the urinary excretion of oxypurines, whereas it decreased the urinary excretion of uric acid and Oxypurinol as well as the fractional excretion of hypoxanthine, xanthine, uric acid, and Oxypurinol. In the exercise-alone experiment, exercise increased the concentrations of purine bases and noradrenaline in plasma, lactic acid in blood, and the urinary excretion of oxypurines, whereas it decreased the urinary excretion of uric acid and fractional excretion of purine bases. In contrast, in the allopurinol-alone experiment, the plasma concentration, urinary excretion, and fractional excretion of purine bases and Oxypurinol remained unchanged. These results suggest that increases in adenine nucleotide degradation and lactic acid production, as well as a release of noradrenaline caused by exercise, contribute to increases in plasma concentration and urinary excretion of oxypurines and plasma concentration of urate, as well as decreases in urinary excretion of uric acid and Oxypurinol, along with fractional excretion of uric acid, Oxypurinol, and xanthine. In addition, they suggest that Oxypurinol does not significantly inhibit the exercise-induced increase in plasma concentration of urate.
-
Effects of angiotensin II infusion on renal excretion of purine bases and Oxypurinol.
Metabolism: clinical and experimental, 2002Co-Authors: Yuji Moriwaki, Sumio Takahashi, Zenta Tsutsumi, Tetsuya Yamamoto, Toshikazu HadaAbstract:The effect of angiotensin II infusion on the renal transport of purine bases and Oxypurinol (a metabolite of allopurinol) was investigated in 5 healthy subjects who were orally given allopurinol (300 mg) 9 hours prior to the study. Angiotensin II was intravenously administered at 8 ng/min/kg for 2 hours. The fractional clearances of uric acid, xanthine, and Oxypurinol were significantly decreased during angiotensin II infusion; however, that of hypoxanthine did not change. The urinary excretion levels of uric acid, xanthine, and Oxypurinol were also significantly decreased during angiotensin II infusion. These results suggest that angiotensin II infusion affected the renal clearances of uric acid, xanthine, and Oxypurinol through direct tubular transport and/or hemodynamic changes. Accordingly, the hypouricemic effect of allopurinol may be exaggerated in hypertensive gout patients with an enhanced renin-angiotensin system, since an increased biological half-life of Oxypurinol is expected in these patients.
-
Effect of norepinephrine on the urinary excretion of purine bases and Oxypurinol
Metabolism, 2001Co-Authors: Tetsuya Yamamoto, Yuji Moriwaki, Sumio Takahashi, Zenta Tsutsumi, Toshikazu HadaAbstract:To examine whether norepinephrine affects the plasma concentrations and urinary excretion of purine bases and Oxypurinol, we orally administered allopurinol (300 mg) to 5 healthy subjects and 9 hours later intravenously administered norepinephrine (12 to 20 [mu ]g/kg body weight), which causes a more than 10 mm Hg increase in diastolic pressure for 2 hours. Norepinephrine decreased the urinary excretion of uric acid by 33% (P [lt ] .01), Oxypurinol by 32% (P [lt ] .01), and xanthine by 51% (P [lt ] .01), as well as the fractional clearance of uric acid by 32% (P [lt ] .01), Oxypurinol by 24% (P [lt ] .05), and xanthine by 21% (P [lt ] .05) when measured 1 to 2 hours after administration. These results indicate that norepinephrine decreases the urinary excretion of uric acid, Oxypurinol, and xanthine, probably via hemodynamic change. It is also suggested that the hypouricemic effect of allopurinol may be more potent than that expected in gout patients with enhanced sympathetic tone, such as in salt-sensitive hypertension.
-
Effect of furosemide on renal excretion of Oxypurinol and purine bases.
Metabolism: clinical and experimental, 2001Co-Authors: Tetsuya Yamamoto, Yuji Moriwaki, Sumio Takahashi, Zenta Tsutsumi, Toshikazu HadaAbstract:To examine whether furosemide affects the plasma concentration and urinary excretion of purine bases and Oxypurinol, we administered allopurinol (300 mg) orally to 6 healthy subjects and then administered furosemide (20 mg) intravenously 10 hours later. Furosemide (20 mg) decreased the urinary excretion of uric acid by 40% (P < .01), Oxypurinol by 39% (P < .05), and xanthine by 43% (P < .05) and the fractional clearance of uric acid by 45% (P < .01) and Oxypurinol by 34% (P < .05) when measured 1 to 2 hours after administration. Moreover, furosemide increased the plasma concentration of uric acid by 6% at 1.5 hours after administration. These results indicate that furosemide may decrease the urinary excretion of uric acid and Oxypurinol by acting on their common renal transport pathway(s). In addition, it is suggested that the effect of furosemide on Oxypurinol is clinically important, since the hypouricemic effect of allopurinol may become more potent as a result.
Yuji Moriwaki - One of the best experts on this subject based on the ideXlab platform.
-
Acute Effects of Oral Tofisopam on Plasma Concentration and Urinary Excretion of Uric Acid and Oxypurinol "Preliminary Communication".
Current clinical pharmacology, 2015Co-Authors: Miki Hatayama, Yuji Moriwaki, Zenta Tsutsumi, Masafumi Kurajoh, Hidenori Koyama, Chihiro Sumida, Jun Shiraishi, Hirokazu Okazaki, Takuhito Shoji, Mitsuyoshi NambaAbstract:The effects of tofisopam, a GABA-receptor agonist, following oral administration (300mg) with and without allopurinol pretreatment on the plasma concentration and renal transport of uric acid and Oxypurinol were investigated in 5 healthy subjects. Fractional and urinary excretions of uric acid were both significantly increased at 2-3 hours after tofisopam administration (559% and 459%, respectively), while plasma uric acid concentration was significantly decreased (36%) at 2.5 hours, suggesting that tofisopam affects uric acid metabolism via the tubular transport system. The hypouricemic effect of tofisopam was comparable to or greater than that of losartan and/or fenofibrate, which also have uric acid-lowering activity. In addition, with prior administration of allopurinol, the fractional and urinary excretions of Oxypurinol were increased at 2-3 hours after tofisopam administration (51% and 33%, respectively), while the plasma Oxypurinol concentration was significantly decreased at 1.5 and 2.5 hours (15% and 21%, respectively). Accordingly, tofisopam may be an attractive compound for treatment of hyperuricemia and/or gout, especially in patients complicated with autonomic dysfunction symptoms, though it is possible that the uric acid-lowering effect of Oxypurinol is attenuated by tofisopam.
-
Effects of bovine milk ingestion on urinary excretion of Oxypurinol and uric acid.
International journal of clinical pharmacology and therapeutics, 2011Co-Authors: Masafumi Kurajoh, Yuji Moriwaki, Zenta Tsutsumi, Chihiro Okuda, Asako Yamamoto, Hidenori Koyama, Tetsuya YamamotoAbstract:Objective Although allopurinol is a xanthine oxidase inhibitor, its overall effect may be due to the action of Oxypurinol, a metabolite of allopurinol and another xanthine oxidase inhibitor, since the biological half-life of Oxypurinol is longer than that of allopurinol. Oxypurinol shares a renal transport pathway with uric acid and ingestion of bovine milk increases the urinary excretion of uric acid. Therefore, we investigated whether its ingestion promotes the urinary excretion of Oxypurinol. Subjects/methods Bovine milk (15 ml/kg body weight) was administered to 6 healthy subjects who took allopurinol (300 mg) 12 h prior to ingestion. In addition, a control experiment was performed with the same subjects using the same protocol, except for the ingestion of water instead of bovine milk. Blood and urine samples were collected before and after bovine and water ingestion. Results In the bovine milk ingestion experiment, the urinary excretion values of Oxypurinol and uric acid were increased by 18% and 38%, respectively, and the fractional excretion values of Oxypurinol and uric acid were increased by 20% and 40%, respectively, whereas those did not change in the control experiment. In addition, the concentration of alanine and sum of concentrations of amino acids were increased by 16% and 20%, respectively, in the bovine milk ingestion experiment. Conclusion These results suggest that bovine milk ingestion promotes the urinary excretion of Oxypurinol as well as uric acid by increasing amino acid concentration.
-
Plasma concentrations and urinary excretion of purine bases (uric acid, hypoxanthine, and xanthine) and Oxypurinol after rigorous exercise.
Metabolism: clinical and experimental, 2006Co-Authors: Mitsuharu Kaya, Yuji Moriwaki, Sumio Takahashi, Zenta Tsutsumi, Asako Yamamoto, Taku Inokuchi, Junzou Tsuzita, Yoshitaka Oku, Tetsuya YamamotoAbstract:Abstract To investigate the effects of exercise on the plasma concentrations and urinary excretion of purine bases and Oxypurinol, we performed 3 experiments with 6 healthy male subjects. The first was a combination of allopurinol intake (300 mg) and exercise (V˙ o 2max, 70%) (combination experiment), the second was exercise alone (exercise-alone experiment), and the third was allopurinol intake alone (allopurinol-alone experiment). In the combination experiment, exercise increased the concentrations of purine bases and noradrenaline in plasma, as well as lactic acid in blood and the urinary excretion of oxypurines, whereas it decreased the urinary excretion of uric acid and Oxypurinol as well as the fractional excretion of hypoxanthine, xanthine, uric acid, and Oxypurinol. In the exercise-alone experiment, exercise increased the concentrations of purine bases and noradrenaline in plasma, lactic acid in blood, and the urinary excretion of oxypurines, whereas it decreased the urinary excretion of uric acid and fractional excretion of purine bases. In contrast, in the allopurinol-alone experiment, the plasma concentration, urinary excretion, and fractional excretion of purine bases and Oxypurinol remained unchanged. These results suggest that increases in adenine nucleotide degradation and lactic acid production, as well as a release of noradrenaline caused by exercise, contribute to increases in plasma concentration and urinary excretion of oxypurines and plasma concentration of urate, as well as decreases in urinary excretion of uric acid and Oxypurinol, along with fractional excretion of uric acid, Oxypurinol, and xanthine. In addition, they suggest that Oxypurinol does not significantly inhibit the exercise-induced increase in plasma concentration of urate.
-
Effects of angiotensin II infusion on renal excretion of purine bases and Oxypurinol.
Metabolism: clinical and experimental, 2002Co-Authors: Yuji Moriwaki, Sumio Takahashi, Zenta Tsutsumi, Tetsuya Yamamoto, Toshikazu HadaAbstract:The effect of angiotensin II infusion on the renal transport of purine bases and Oxypurinol (a metabolite of allopurinol) was investigated in 5 healthy subjects who were orally given allopurinol (300 mg) 9 hours prior to the study. Angiotensin II was intravenously administered at 8 ng/min/kg for 2 hours. The fractional clearances of uric acid, xanthine, and Oxypurinol were significantly decreased during angiotensin II infusion; however, that of hypoxanthine did not change. The urinary excretion levels of uric acid, xanthine, and Oxypurinol were also significantly decreased during angiotensin II infusion. These results suggest that angiotensin II infusion affected the renal clearances of uric acid, xanthine, and Oxypurinol through direct tubular transport and/or hemodynamic changes. Accordingly, the hypouricemic effect of allopurinol may be exaggerated in hypertensive gout patients with an enhanced renin-angiotensin system, since an increased biological half-life of Oxypurinol is expected in these patients.
-
Effect of norepinephrine on the urinary excretion of purine bases and Oxypurinol
Metabolism, 2001Co-Authors: Tetsuya Yamamoto, Yuji Moriwaki, Sumio Takahashi, Zenta Tsutsumi, Toshikazu HadaAbstract:To examine whether norepinephrine affects the plasma concentrations and urinary excretion of purine bases and Oxypurinol, we orally administered allopurinol (300 mg) to 5 healthy subjects and 9 hours later intravenously administered norepinephrine (12 to 20 [mu ]g/kg body weight), which causes a more than 10 mm Hg increase in diastolic pressure for 2 hours. Norepinephrine decreased the urinary excretion of uric acid by 33% (P [lt ] .01), Oxypurinol by 32% (P [lt ] .01), and xanthine by 51% (P [lt ] .01), as well as the fractional clearance of uric acid by 32% (P [lt ] .01), Oxypurinol by 24% (P [lt ] .05), and xanthine by 21% (P [lt ] .05) when measured 1 to 2 hours after administration. These results indicate that norepinephrine decreases the urinary excretion of uric acid, Oxypurinol, and xanthine, probably via hemodynamic change. It is also suggested that the hypouricemic effect of allopurinol may be more potent than that expected in gout patients with enhanced sympathetic tone, such as in salt-sensitive hypertension.
Sumio Takahashi - One of the best experts on this subject based on the ideXlab platform.
-
Plasma concentrations and urinary excretion of purine bases (uric acid, hypoxanthine, and xanthine) and Oxypurinol after rigorous exercise.
Metabolism: clinical and experimental, 2006Co-Authors: Mitsuharu Kaya, Yuji Moriwaki, Sumio Takahashi, Zenta Tsutsumi, Asako Yamamoto, Taku Inokuchi, Junzou Tsuzita, Yoshitaka Oku, Tetsuya YamamotoAbstract:Abstract To investigate the effects of exercise on the plasma concentrations and urinary excretion of purine bases and Oxypurinol, we performed 3 experiments with 6 healthy male subjects. The first was a combination of allopurinol intake (300 mg) and exercise (V˙ o 2max, 70%) (combination experiment), the second was exercise alone (exercise-alone experiment), and the third was allopurinol intake alone (allopurinol-alone experiment). In the combination experiment, exercise increased the concentrations of purine bases and noradrenaline in plasma, as well as lactic acid in blood and the urinary excretion of oxypurines, whereas it decreased the urinary excretion of uric acid and Oxypurinol as well as the fractional excretion of hypoxanthine, xanthine, uric acid, and Oxypurinol. In the exercise-alone experiment, exercise increased the concentrations of purine bases and noradrenaline in plasma, lactic acid in blood, and the urinary excretion of oxypurines, whereas it decreased the urinary excretion of uric acid and fractional excretion of purine bases. In contrast, in the allopurinol-alone experiment, the plasma concentration, urinary excretion, and fractional excretion of purine bases and Oxypurinol remained unchanged. These results suggest that increases in adenine nucleotide degradation and lactic acid production, as well as a release of noradrenaline caused by exercise, contribute to increases in plasma concentration and urinary excretion of oxypurines and plasma concentration of urate, as well as decreases in urinary excretion of uric acid and Oxypurinol, along with fractional excretion of uric acid, Oxypurinol, and xanthine. In addition, they suggest that Oxypurinol does not significantly inhibit the exercise-induced increase in plasma concentration of urate.
-
Effects of angiotensin II infusion on renal excretion of purine bases and Oxypurinol.
Metabolism: clinical and experimental, 2002Co-Authors: Yuji Moriwaki, Sumio Takahashi, Zenta Tsutsumi, Tetsuya Yamamoto, Toshikazu HadaAbstract:The effect of angiotensin II infusion on the renal transport of purine bases and Oxypurinol (a metabolite of allopurinol) was investigated in 5 healthy subjects who were orally given allopurinol (300 mg) 9 hours prior to the study. Angiotensin II was intravenously administered at 8 ng/min/kg for 2 hours. The fractional clearances of uric acid, xanthine, and Oxypurinol were significantly decreased during angiotensin II infusion; however, that of hypoxanthine did not change. The urinary excretion levels of uric acid, xanthine, and Oxypurinol were also significantly decreased during angiotensin II infusion. These results suggest that angiotensin II infusion affected the renal clearances of uric acid, xanthine, and Oxypurinol through direct tubular transport and/or hemodynamic changes. Accordingly, the hypouricemic effect of allopurinol may be exaggerated in hypertensive gout patients with an enhanced renin-angiotensin system, since an increased biological half-life of Oxypurinol is expected in these patients.
-
Effect of norepinephrine on the urinary excretion of purine bases and Oxypurinol
Metabolism, 2001Co-Authors: Tetsuya Yamamoto, Yuji Moriwaki, Sumio Takahashi, Zenta Tsutsumi, Toshikazu HadaAbstract:To examine whether norepinephrine affects the plasma concentrations and urinary excretion of purine bases and Oxypurinol, we orally administered allopurinol (300 mg) to 5 healthy subjects and 9 hours later intravenously administered norepinephrine (12 to 20 [mu ]g/kg body weight), which causes a more than 10 mm Hg increase in diastolic pressure for 2 hours. Norepinephrine decreased the urinary excretion of uric acid by 33% (P [lt ] .01), Oxypurinol by 32% (P [lt ] .01), and xanthine by 51% (P [lt ] .01), as well as the fractional clearance of uric acid by 32% (P [lt ] .01), Oxypurinol by 24% (P [lt ] .05), and xanthine by 21% (P [lt ] .05) when measured 1 to 2 hours after administration. These results indicate that norepinephrine decreases the urinary excretion of uric acid, Oxypurinol, and xanthine, probably via hemodynamic change. It is also suggested that the hypouricemic effect of allopurinol may be more potent than that expected in gout patients with enhanced sympathetic tone, such as in salt-sensitive hypertension.
-
Effect of furosemide on renal excretion of Oxypurinol and purine bases.
Metabolism: clinical and experimental, 2001Co-Authors: Tetsuya Yamamoto, Yuji Moriwaki, Sumio Takahashi, Zenta Tsutsumi, Toshikazu HadaAbstract:To examine whether furosemide affects the plasma concentration and urinary excretion of purine bases and Oxypurinol, we administered allopurinol (300 mg) orally to 6 healthy subjects and then administered furosemide (20 mg) intravenously 10 hours later. Furosemide (20 mg) decreased the urinary excretion of uric acid by 40% (P < .01), Oxypurinol by 39% (P < .05), and xanthine by 43% (P < .05) and the fractional clearance of uric acid by 45% (P < .01) and Oxypurinol by 34% (P < .05) when measured 1 to 2 hours after administration. Moreover, furosemide increased the plasma concentration of uric acid by 6% at 1.5 hours after administration. These results indicate that furosemide may decrease the urinary excretion of uric acid and Oxypurinol by acting on their common renal transport pathway(s). In addition, it is suggested that the effect of furosemide on Oxypurinol is clinically important, since the hypouricemic effect of allopurinol may become more potent as a result.
-
Effect of fenofibrate on plasma concentration and urinary excretion of purine bases and Oxypurinol
The Journal of rheumatology, 2001Co-Authors: Tetsuya Yamamoto, Yuji Moriwaki, Sumio Takahashi, Zenta Tsutsumi, Toshikazu HadaAbstract:OBJECTIVE: To investigate whether fenofibrate increases the clearance of purine bases (hypoxanthine, xanthine, uric acid) and Oxypurinol. METHODS: We administered fenofibrate (150 mg) 3 times a day for 3 days, and then allopurinol (300 mg) 4 h after the last administration of fenofibrate, to 5 healthy subjects. Ten hours later, a clearance study was done. RESULTS: Following 3 day administration of fenofibrate, fractional clearance of xanthine, uric acid, and Oxypurinol increased by 41% (p < 0.05), 101% (p < 0.01), and 51% (p < 0.01), respectively, compared to baseline values, while the respective plasma concentrations decreased by 46% (p < 0.05), 46% (p < 0.05), and 19% (p < 0.05). CONCLUSION: Our results suggest that fenofibrate, fenofibric acid, or fenofibrate derivatives can increase fractional clearance of xanthine, uric acid, and Oxypurinol by acting on their common renal pathways. It is suggested that the hypouricemic effect of combination therapy using allopurinol and fenofibrate may be less than additive.
Richard O. Day - One of the best experts on this subject based on the ideXlab platform.
-
an audit of a therapeutic drug monitoring service for allopurinol therapy
Therapeutic Drug Monitoring, 2013Co-Authors: Diluk R W Kannangara, Garry G. Graham, Kenneth M. Williams, Sheena N Ramasamy, John E Ray, Graham R D Jones, Richard O. DayAbstract:BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
-
Oxypurinol, allopurinol and allopurinol-1-riboside in plasma following an acute overdose of allopurinol in a patient with advanced chronic kidney disease
British journal of clinical pharmacology, 2012Co-Authors: Diluk R W Kannangara, Garry G. Graham, Kenneth M. Williams, Darren M. Roberts, Timothy J. Furlong, Richard O. DayAbstract:Allopurinol is used to prevent gout. It is metabolized by xanthine oxidoreductase to Oxypurinol, itself a xanthine oxidoreductase inhibitor, thereby reducing urate formation. It may also be metabolized by aldehyde oxidase to Oxypurinol [1]. Another metabolite of allopurinol is allopurinol-1-riboside, formed directly by the enzyme purine nucleoside phosphorylase or indirectly through the dephosphorylation of allopurinol-1-ribotide [2]. An acute overdose of allopurinol can have contrasting outcomes. Severe reactions were reported in two cases [3], [4], while no reaction was reported in one case [5]. Allopurinol and Oxypurinol are renally excreted, so renal impairment would reduce its clearance and possibly potentiate acute toxicity. However, the effect of renal impairment on clinical outcomes following an acute overdose has not been described. We report a case of allopurinol overdose in a patient with advanced chronic kidney disease. The case is of interest because accumulation of Oxypurinol during routine dosing in renal failure has been considered a risk factor for severe allopurinol toxicity, including Stevens–Johnson syndrome and toxic epidermal necrolysis [6], which have mortalities of 30–50%. A 36-year-old transgender woman presented to hospital 30 min after ingesting 10 g allopurinol. The patient selected allopurinol because Internet information indicated low toxicity in overdose. There were no abnormal clinical signs on presentation and no adverse sequelae. She was discharged within 24 h. The medical history included an overdose of allopurinol 2 years earlier (Oxypurinol concentration 44 mg l−1; time after allopurinol ingestion unknown), from which she also suffered no adverse effects. Her medical history also included gout (20 years), hypertension, hypercholesterolaemia and advanced chronic kidney disease [creatinine 493 µm; estimated glomerular filtration rate of 10–12 ml min−1 (1.73 m)−2] due to focal segmental glomerulosclerosis. The patient was reportedly taking allopurinol 100 mg day−1 prior to the overdose. Other medications included perindopril and rosuvastatin, as well as synthetic oestrogens. Urine screening was positive for opiates, benzodiazepines and amphetamines. She consented to return over the next week for additional blood tests. Allopurinol, Oxypurinol and allopurinol-1-riboside concentrations were determined by high-performance liquid chromatography. The assay is validated for Oxypurinol [7], and standard curves for all analytes were linear (r2 > 0.999). The identity and purity of each analyte was confirmed by comparison of retention times against standards and by scanning UV spectrophotometry of the peaks. Apparent elimination half-lives (t1/2) were estimated by nonlinear regression, assuming a one-compartment model. The t1/2 of Oxypurinol was 65 h, considerably longer than found in healthy subjects (approximately 24 h) [1]. The longer t1/2 is attributed to the impaired renal function of this patient, as Oxypurinol is renally excreted [1]. The peak plasma concentration (Cmax) of Oxypurinol in this patient was 106 mg l−1. The apparent elimination t1/2 of allopurinol was 4.4 h. Again, this is longer than the t1/2 (1.2 ± 0.3 h) in healthy subjects [1], possibly due to saturation of xanthine oxidoreductase. The patient's poor renal function may also have contributed to slower elimination, although renal clearance usually accounts for only approximately 10% of an oral dose of allopurinol [1]. The Cmax of allopurinol following a therapeutic dose of allopurinol (300 mg) is about 3 mg l−1,[1]. By contrast, the Cmax in this patient was much higher, at 29 mg l−1 (Figure 1). Figure 1 Time courses of allopurinol, Oxypurinol and allopurinol-1-riboside after an overdose of allopurinol (10 g). Oxypurinol (); Allopurinol (); Allopurinol-1-riboside () Approximately 10% of allopurinol is excreted as allopurinol-1-riboside [1]. The t1/2 of the allopurinol-1- riboside is approximately 3 h following dosage of the riboside itself [8]. We found substantial concentrations of the riboside (up to 19 mg l−1). Given its high aqueous solubility, its renal excretion may be delayed in chronic kidney disease. One of the three previously reported cases of acute allopurinol overdose died from hepatic centrilobular necrosis. The dose of allopurinol was unknown, but the plasma concentration was recorded as 231 mg l−1, which is much greater than the value for our patient (29 mg l−1). The assay details were, however, not presented, and it is unclear whether Oxypurinol or allopurinol was measured. Other causes of the hepatotoxicity may have been concurrent use of indomethacin and captopril [3]. Another patient who ingested 20 g allopurinol developed a variety of toxic effects, including hepatitis, leukopaenia, fever and diarrhoea but recovered with supportive care [4]. By contrast, in a third case, no adverse effects following the ingestion of approximately 20 g allopurinol were reported. The Oxypurinol concentration for this latter subject was approximately 43 mg l−1 at approximately 12 h and the elimination half-life was 26 h [5]. By comparison, in our patient who purportedly took 10 g allopurinol, the estimated plasma concentration of Oxypurinol at 12 h was approximately 100 mg l−1 (Figure 1). It is not known why there was no clinical toxicity. In the two cases where toxicity was reported, involvement of other drugs may have been contributory. The relationship between plasma concentrations of Oxypurinol and adverse reactions is still unclear. Further investigation is required to clarify these observations. In summary, it is unclear whether or not adverse effects from acute overdoses of allopurinol are expected. Despite high concentrations of allopurinol and metabolites, our patient was largely unaffected by the overdose. Renal impairment appears to have contributed to the delayed elimination of allopurinol and its metabolites.
-
pharmacokinetic and pharmacodynamic interaction between allopurinol and probenecid in patients with gout
The Journal of Rheumatology, 2011Co-Authors: Sophie L. Stocker, Andrew J. Mclachlan, Garry G. Graham, Kenneth M. Williams, Richard O. DayAbstract:Objective. To investigate the pharmacokinetic and pharmacodynamic interaction between probenecid and Oxypurinol (the active metabolite of allopurinol) in patients with gout. Methods. 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. Results. 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 Conclusion. 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.
-
measurement of urinary Oxypurinol by high performance liquid chromatography tandem mass spectrometry
Journal of Chromatography B, 2010Co-Authors: Sophie L. Stocker, Richard O. Day, Andrew J. Mclachlan, Kenneth M. Williams, Michael E Franklin, Jacqueline M Anderson, Peter I Pillans, Paul J TaylorAbstract: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.
-
Measurement of urinary Oxypurinol by high performance liquid chromatography-tandem mass spectrometry
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2010Co-Authors: Sophie L. Stocker, Richard O. Day, Andrew J. Mclachlan, Kenneth M. Williams, Michael E Franklin, Jacqueline M Anderson, Peter I Pillans, Paul J TaylorAbstract: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
Peter T Chapman - One of the best experts on this subject based on the ideXlab platform.
-
relationships between allopurinol dose Oxypurinol concentration and urate lowering response in search of a minimum effective Oxypurinol concentration
Clinical and Translational Science, 2020Co-Authors: Lisa K Stamp, Peter T Chapman, Murray L Barclay, Anne Horne, Chris Frampton, Tony R Merriman, Daniel F B Wright, Jill Drake, Nicola DalbethAbstract: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).
-
Relationships Between Allopurinol Dose, Oxypurinol Concentration and Urate‐Lowering Response—In Search of a Minimum Effective Oxypurinol Concentration
Clinical and translational science, 2019Co-Authors: Lisa K Stamp, Peter T Chapman, Murray L Barclay, Anne Horne, Chris Frampton, Tony R Merriman, Daniel F B Wright, Jill Drake, Nicola DalbethAbstract: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
-
A population pharmacokinetic model to predict Oxypurinol exposure in patients on haemodialysis.
European journal of clinical pharmacology, 2016Co-Authors: Daniel F B Wright, Peter T Chapman, Murray L Barclay, Matthew P. Doogue, Nicholas B. Cross, John H Irvine, Lisa K StampAbstract:Purpose The aims of this study were to characterise the population pharmacokinetics of Oxypurinol in patients receiving haemodialysis and to compare Oxypurinol exposure in dialysis and non-dialysis patients.
-
implications
2016Co-Authors: Lisa K Stamp, Murray L Barclay, Jill Drake, Mei Zhang, John L. O’donnell, Christopher Frampton, Peter T ChapmanAbstract:Furosemide increases plasma Oxypurinol without lowering serum urate—a complex drug interaction
-
furosemide increases plasma Oxypurinol without lowering serum urate a complex drug interaction implications for clinical practice
Rheumatology, 2012Co-Authors: Lisa K Stamp, Murray L Barclay, Chris Frampton, Jill Drake, Mei Zhang, John L Odonnell, Peter T ChapmanAbstract:Objective To determine the effects of furosemide on serum urate (SU), plasma Oxypurinol and urinary urate. Methods 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. Results 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. Conclusion 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. Trial registration Australian New Zealand Clinical Trials Registry, www.anzctr.org.au, 12609000529246.
