The metabolism of ribavirin in erythrocytes and nucleated cells

Page, Theodore; Connor, James D.

doi:10.1016/0020-711x(90)90140-x

Cited by 124 publications

(117 citation statements)

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“…[14][15][16] Adenosine kinase has been identified as the enzyme responsible for RBV phosphorylation, as shown by the absence of RBV phosphorylation in cells lacking this enzyme. 15,16 RBV phosphates are unable to cross the erythrocyte membrane. In addition, the enzymes 5Ј-nucleotidases and alkaline phosphatase, which can hydrolyze RBV phosphates, are present in most nucleated cells as well as in human serum, but they are absent in human erythrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…13 RBV is converted intracellularly to the corresponding triphosphate, producing a relative adenosine triphosphate (ATP) deficiency in erythrocytes. [14][15][16] The lowering ATP level might indirectly affect the antioxidant defense mechanisms, by decreasing hexokinase-mediated production of glucose 6-phosphate, a common key substrate for glycolysis and pentosephosphate shunt. Furthermore, RBV is an inhibitor of the inosine dehydrogenase enzyme, which catalyzes the oxidation of inosine 5Ј monophosphate to xanthosine 5Ј monophosphate, with concomitant reduction of nicotinamide adenine dinucleotide to thio-nicotinamide adenine dinucleotide.…”

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Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: Role of membrane oxidative damage

et al. 2000

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The antiviral drug ribavirin (RBV) is widely used in combination with interferon (IFN) in the treatment of chronic hepatitis C virus (HCV) infection. A major side effect of RBV is a reversible hemolytic anemia. We have evaluated the in vitro effects of RBV on erythrocyte adenosine triphosphate (ATP) content and on hexosemonophosphate shunt (HMS). The ATP levels were significantly decreased in the presence of RBV and the HMS was increased, suggesting the presence of red cell susceptibility to oxidation. In vivo, we have studied the hematologic effects of treatment with RBV alone or in combination with IFN in 11 patients with chronic hepatitis C: 6 were treated with RBV (1,000-1,200 mg/d) and 5 were treated with a combination of RBV and IFN (5 million U thrice weekly). Patients were studied at semi-monthly intervals from 0 to day 60 of therapy. Both treatments were associated with a significant reduction in hemoglobin levels (steady state level at day 45) and a marked increase in absolute reticulocyte counts. Erythrocyte Na-K pump activity was significantly diminished, whereas K-Cl cotransport and its dithiotreitol-sensitive fraction, malondialdehyde and methemoglobin levels were significantly increased. RBV-treated patients showed an increase in aggregated band 3, which was associated with a significantly increased binding of autologous antibodies and complement C3 fragments indicating an erithrophagocytic removal by reticuloendothelial system. (HEPATOLOGY 2000;31:997-1004.)Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma worldwide. 1,2 A major therapeutic goal in HCV-infected patients is to achieve early eradication of the virus, and to prevent severe long-term clinical complications. Interferon alfa (IFN-␣) is currently the only therapy that has been shown to have beneficial effects in chronic hepatitis type C. However, with a standard regimen of 3 million U administered 3 times per week for 6 to 12 months, only a small fraction of approximately 15% to 20% of the patients showed a sustained response with normalization of serum alanine transferase levels and serum HCV-RNA clearance. 3 Ribavirin (1-␤-D-ribofuranosyl-1H-1, 2,4-triazole-3-carboxamide) (RBV) is a water soluble synthetic guanosine analog that exerts antiviral activity against DNA and RNA viruses after intracellular phosphorylation. 4 Current studies indicate that combination therapy with RBV and IFN is associated with higher rates of sustained virological, biochemical, and histological response compared to IFN monotherapy. [5][6][7][8][9][10] The major side effect of RBV treatment is the occurrence of a reversible hemolytic anemia in a substantial proportion of treated patients. 11 The underlying mechanism is unknown. Studies on steady-state pharmacokinetics of RBV have shown that erythrocyte concentration of RBV greatly exceeds plasma concentrations 12 and that RBV is a transported permeant for the (es) nucleoside transporter in human erythrocytes...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: Role of membrane oxidative damage

et al. 2000

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“…3 RBV actively enters cells by way of the es-nucleoside membrane transporter 4 and subsequently undergoes phosphorylation at the expense of adenosyl triphosphate (ATP). 5,6 In contrast to nucleated cells such as hepatocytes, phosphorylation is irreversible in the anucleate erythrocytes, and phosphorylated RBV accumulates because it cannot be exported by the nucleoside carrier. Therefore, the concentration of RBV in erythrocytes is 50-to 70-fold higher than the therapeutic plasma concentration of 9 -15 M. 5,7,8 The high concentration of RBV in erythrocytes is probably responsible for the hemolysis occurring during RBV therapy.…”

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confidence: 99%

Low membrane protein sulfhydrils but not G6PD deficiency predict ribavirin-induced hemolysis in hepatitis C

et al. 2004

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Hemolysis is a frequent adverse effect of ribavirin (RBV). It has been suggested that oxidative stress plays a role, but mechanisms and predictive risk factors for severe forms remain unknown. Markers of redox status were determined in erythrocytes of 34 patients with hepatitis C-four of them with glucose-6-phosphate-dehydrogenase (G6PD) deficiencybefore and during treatment with RBV and interferon (IFN) and were compared with 10 healthy control subjects. In addition, erythrocytes were incubated with RBV, and the effects of dipyridamole (DPD), diethylmaleate (DEM), and glutathione ester (GSHE) were studied in vitro. Of the 30 patients without G6PD deficiency who were treated with RBV and IFN-␣, five developed major hemolysis (⌬ hemoglobin > 6 g/dL) and 25 developed minor hemolysis (⌬ hemoglobin < 2.5 g/dL). Patients with major hemolysis had lower median pretreatment values of membrane protein sulfhydrils than patients with minor hemolysis (28.4 vs. 36.7 nmol/mg, P < .001). Erythrocytes of G6PD-deficient patients were not more susceptible to RBV-induced hemolysis. In in vitro incubations of erythrocytes, DEM enhanced the RBV-induced decrease of glutathione, protein sulfhydrils, and osmotic resistance. Supplementation of GSHE and DPD prevented the RBV-induced decrease in osmotic resistance, adenosyl triphosphate (ATP), and 2,3-diphosphoglycerate (DPG), the loss of glutathione and protein sulfhydrils, and the formation of thiobarbituric acid reactive substances (TBARs). In conclusion, the data indicate that low membrane protein sulfhydrils prior to therapy but not G6PD deficiency are predictive of RBV-induced major hemolysis. In vitro, GSHE and DPD reduce the RBV-associated oxidative stress in erythrocytes and prevent the increase in osmotic fragility, suggesting that these compounds might decrease the risk of hemolysis in patients. (HEPATOLOGY 2004;39:1248 -1255 R ibavirin (RBV) is a synthetic nucleoside analogue used in the treatment of chronic hepatitis C in combination with interferon (IFN)-␣. The addition of RBV has increased the probability of sustained response to approximately 40% if combined with conventional IFN 1,2 and to over 50% if combined with pegylated IFN. 3 RBV actively enters cells by way of the es-nucleoside membrane transporter 4 and subsequently undergoes phosphorylation at the expense of adenosyl triphosphate (ATP). 5,6 In contrast to nucleated cells such as hepatocytes, phosphorylation is irreversible in the anucleate erythrocytes, and phosphorylated RBV accumulates because it cannot be exported by the nucleoside carrier. Therefore, the concentration of RBV in erythrocytes is 50-to 70-fold higher than the therapeutic plasma concentration of 9 -15 M. 5,7,8 The high concentration of RBV in erythrocytes is probably responsible for the hemolysis occurring during RBV therapy. A decrease in hemoglobin (HB) is frequently observed in patients who receive RBV,

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“…Then, at 0.5 g/ml of ribavirin and at an MOI of ISAV of 0.01, a percentage of polymerase complexes remains active. Thus, once the ribavirin is metabolized and/or eliminated from the cell (within 24 h of removal from the medium [31,34]), the transcription and subsequent replication of the viral genome could begin, completing the infective cycle and allowing detection of RNA in the supernatant of the culture.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effect of a Nucleotide Analog on Infectious Salmon Anemia Virus Infection

Rivas‐Aravena

Vallejos‐Vidal²,

Martı́n

et al. 2011

J Virol

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The infectious salmon anemia virus (ISAV), which belongs to the Orthomyxoviridae family, has been responsible for major losses in the salmon industry, with mortalities close to 100% in areas where Atlantic salmon (Salmo salar) is grown. This work studied the effect of ribavirin (1-␤-D-ribofuranosyl-1,2,3-triazole-3-carbaxaide), a broad-spectrum antiviral compound with proven ability to inhibit the replicative cycle of the DNA and RNA viruses. The results show that ribavirin was able to inhibit the infectivity of ISAV in in vitro assays. In these assays, a significant inhibition of the replicative viral cycle was observed with a 50% inhibitory concentration (IC 50 ) of 0.02 g/ml and an IC 90 of 0.4 g/ml of ribavirin. After ribavirin treatment, viral proteins were not detectable and a reduction of viral mRNA association with ribosomes was observed. Ribavirin does not affect the levels of EF1a, nor its association with polysomes, suggesting that the inhibition of RNA synthesis occurs specifically for the virus mRNAs and not for cellular mRNAs. Moreover, ribavirin caused a significant reduction in genomic and viral RNA messenger levels. The study of the inhibitory mechanism showed that it was not reversed by the addition of guanosine. Furthermore, in vivo assays showed a reduction in the mortality of Salmo salar by more than 90% in fish infected with ISAV and treated with ribavirin without adverse effects. In fact, these results show that ribavirin is an antiviral that could be used to prevent ISAV replication either in vitro or in vivo.

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The metabolism of ribavirin in erythrocytes and nucleated cells

Cited by 124 publications

References 7 publications

Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: Role of membrane oxidative damage

Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: Role of membrane oxidative damage

Low membrane protein sulfhydrils but not G6PD deficiency predict ribavirin-induced hemolysis in hepatitis C

Inhibitory Effect of a Nucleotide Analog on Infectious Salmon Anemia Virus Infection

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