Effect of furosemide on renal excretion of oxypurinol and purine bases

doi:10.1053/meta.2001.19489

Metabolism

Volume 50, Issue 2, February 2001, Pages 241-245

https://doi.org/10.1053/meta.2001.19489 Get rights and content

Abstract

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.

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Cited by (21)

Uric acid analogue as a possible xenobiotic marker of uric acid transporter Urat1 in rats
2019, Drug Metabolism and Pharmacokinetics
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Therefore, oxypurinol was considered appropriate for our purpose and evaluated in the following in vivo experiments as a uric acid analogue, since it is an unmetabolized substrate of rUrat1 and is unlikely secretion dominant. When oxypurinol was administered to rats, FE was 0.4, suggesting that oxypurinol is reabsorbed in accordance with the results of transcellular transport assay of oxypurinol in URAT1/GLUT9 cells (Supplemental Fig. 2) and previous report in human [11,12]. Plasma concentration of uric acid was not affected by oxypurinol, suggesting that its concentration is too low to exhibit pharmacological effect as xanthine oxidase inhibitor under this condition.
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.
Molecular mechanism of an adverse drug-drug interaction of allopurinol and furosemide in gout treatment
2014, Biochemical and Biophysical Research Communications
Citation Excerpt :
Belonging to the class of loop diuretics, furosemide primarily acts by inhibiting NKCC2, the luminal Na+/K+/2Cl- symporter in the thick ascending limb of the loop of Henle. Studies have shown that the combination of furosemide and oxypurinol decreases the urinary excretion of uric acid and oxypurinol [5], and initially it was speculated that this interaction might render the hypouricemic effect of allopurinol more potent. A more recent clinical report by Stamp and co-workers [1] showed that patients receiving allopurinol and furosemide indeed exhibited increased plasma oxypurinol levels as well as increased SU.
Gout patients receiving a combination of allopurinol and furosemide require higher allopurinol doses to achieve the target serum urate (SU) of <6 mg/dl (Stamp et al., 2012) [1]. Our study aimed to identify the molecular basis for this observation. We used a fluorimetric assay to determine the impact of furosemide and oxypurinol (the active metabolite of allopurinol) on xanthine oxidase (XO) activity. Immunoblot analysis quantified expression of XO and AMP-kinase (AMPK) in drug-treated human liver (HepG2) and primary kidney (HRCE) cells. In silico analysis identified miR-448 as a potential XO-regulator, whose expression level in HepG2 cells was examined by qPCR.
Fluorimetric experiments revealed no direct interactions between XO and furosemide, nor did the combination of oxypurinol/furosemide alter the XO inhibition profile of oxypurinol. In HepG2 cells, we found a significant decrease in XO protein expression following oxypurinol treatment, which was abolished after co-incubation with furosemide. Probenecid alone or in combination with furosemide reduced XO protein expression significantly. qPCR analysis of miR-448 in HepG2 cells mirrored the drug-dependent changes in XO protein expression. In addition, oxypurinol and the combination of oxypurinol/furosemide significantly down-regulated AMPK protein expression in HRCE cells.
In conclusion, we show for the first time that besides the established effects of allopurinol on the purine synthetic pathway the efficiency of allopurinol treatment of gout patients is based on two further complementary mechanisms, the direct inhibition of XO activity by the allopurinol metabolite oxypurinol and a down-regulation of XO protein expression. The latter is compromised by addition of furosemide and might explain why patients receiving furosemide therapy require higher allopurinol doses. miR-448 was identified as a potential drug-dependent XO regulator. Finally, down-regulation of AMPK protein expression in HRCE cells by administration of oxypurinol/furosemide reveals a possible new mechanism of renal drug-induced hyperuricemia.
Safety of Urate-Lowering Therapies. Managing the Risks to Gain the Benefits.
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This effect occurs relatively quickly after the initiation of the diuretic and lasts throughout its use.41 Diuretic use has been implicated in AHS and other ADRs as a result of decreased excretion of oxypurinol.42,43 Understandably, if oxypurinol levels do contribute to ADRs, it would be prudent to minimize the levels.
Xanthine oxidase inhibitor treatment of hyperuricemia
2012, Gout and Other Crystal Arthropathies
Xanthine oxidase inhibitor treatment of hyperuricemia
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Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel
2008, Journal of the American Academy of Dermatology
Citation Excerpt :
A drug interaction between allopurinol and other medications, including aminopenicillins, angiotensin-converting enzyme inhibitors, and acetylsalicylic acid or other salicylates, has been suspected to play a role in allopurinol-induced eruptions.1 The literature has focused also on interactions between allopurinol and diuretic agents in view of diuretic-induced hyperuricemia19 and furosemide-induced decreased urinary excretion of oxipurinol.20 Based on the results of the EuroSCAR study, it appears that exposure to furosemide, or diuretics in general, increased the likelihood of taking allopurinol, but was not associated with an increased risk for SJS or TEN.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe cutaneous adverse reactions.
We sought to update knowledge on the causes of SJS or TEN with a focus on the rate of allopurinol-associated cases and to identify risk factors for allopurinol-associated SJS or TEN.
We conducted a multinational case-control study.
In all, 379 patients with severe cutaneous adverse reactions validated as SJS or TEN and 1505 matched hospitalized control subjects were enrolled. Allopurinol was the drug most frequently associated with SJS or TEN, with 66 exposed patients (17.4%) and 28 exposed control subjects (1.9%) (adjusted odds ratio = 18, 95% confidence interval: 11-32). Allopurinol use was greater than in a previous case-control European study. Daily doses equal to or greater than 200 mg were associated with a higher risk (adjusted odds ratio = 36, 95% confidence interval: 17-76) than lower doses (adjusted odds ratio = 3.0, 95% confidence interval: 1.1-8.4). The risk was restricted to short-term use (≤8 weeks). The use of comedications did not increase the risk.
Nonsystematic recording of the indications for allopurinol use was a limitation.
Results of this multinational study (EuroSCAR) revealed that allopurinol is the drug most commonly associated with SJS or TEN. The incidence of allopurinol-associated SJS or TEN has increased possibly because of increased use and dosages of this drug.

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