Marked elevation of erythrocyte ribavirin levels in interferon and ribavirin-induced anemia

Homma, Masato; Matsuzaki, Yasushi; Inoue, Yoichi; Shibata, Minoru; Mitamura, Keiji; Tanaka, Naomi; Kohda, Yukinao

doi:10.1016/s1542-3565(04)00064-3

Cited by 52 publications

(57 citation statements)

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“…We found that week 4 hemoglobin declines were significantly greater in SVRs compared with NRs. In agreement with our results, two recent studies found that erythrocyte RBV levels correlate with hemoglobin reductions at weeks 2 -4 in IFN alfa-2b/RBV treated monoinfected patients [32,33]. In contrast, another recent study did not observe differences in RBV levels comparing SVRs and NRs [34].…”

Section: Discussionsupporting

confidence: 92%

Early ribavirin pharmacokinetics, HCV RNA and alanine aminotransferase kinetics in HIV/HCV co-infected patients during treatment with pegylated interferon and ribavirin

Dahari¹,

Markatou²,

Zeremski³

et al. 2007

Journal of Hepatology

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Section: Discussionsupporting

confidence: 92%

Early ribavirin pharmacokinetics, HCV RNA and alanine aminotransferase kinetics in HIV/HCV co-infected patients during treatment with pegylated interferon and ribavirin

Dahari¹,

Markatou²,

Zeremski³

et al. 2007

Journal of Hepatology

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“…These intracellular levels for ribavirin corresponded to the steady state erythrocyte levels (800-1600 mM) in HCV patients receiving ribavirin. 9,10) Since erythrocyte ribavirin concentration Ͼ1000 mM has been reported a risk for ribavirininduced anemia, 10) it is interesting to compare the ribavirintreated erythrocytes with and without dipyridamole in terms of intracellular ribavirin of lower and higher than 1000 mM, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…9,10) Recent studies have revealed that erythrocyte ribavirin induced intracellular ATP deficiency, leading to downregulation of the hexose monophosphate shunt resulting in accelerated oxidative damage on erythrocyte cell membrane.…”

mentioning

confidence: 99%

“…[9][10][11][12] Once incorporated into erythrocytes via es-type nucleoside transporter, 13) ribavirin is subjected to intracellular phosphorylation and converted to its phosphorylated metabolites. 14) Therefore the concentration of erythrocyte ribavirin including phosphorylated metabolites is 160-fold higher than that in plasma.…”

mentioning

confidence: 99%

“…14) Therefore the concentration of erythrocyte ribavirin including phosphorylated metabolites is 160-fold higher than that in plasma. 9,10) Recent studies have revealed that erythrocyte ribavirin induced intracellular ATP deficiency, leading to downregulation of the hexose monophosphate shunt resulting in accelerated oxidative damage on erythrocyte cell membrane. 15) Significant alterations including band 3 aggregation were also found; these are known associated with erythrophagocytosis in reticuloendothelial system (RES).…”

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confidence: 99%

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Morphological Transformation and Phosphatidylserine Exposure in Erythrocytes Treated with Ribavirin

Homma

Hosono

Hasegawa³

et al. 2009

Biological & Pharmaceutical Bulletin

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Ribavirin (1-b -D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide), a synthetic guanosine analogue, is phosphorylated intracellularly to exert antiviral activities against DNA and RNA viruses.1,2) Combination therapy with interferon (IFN) for hepatitis C virus (HCV) infection revealed that higher rate of sustained virus response was achieved by adjuvant effects of ribavirin. [3][4][5] One of the major side effects of ribavirin is a reversible hemolytic anemia, which sometimes necessitates cessation of ribavirin co-administration. [6][7][8] Ribavirin-induced hemolytic anemia is likely due to excessive accumulation of phosphorylated ribavirin in erythrocytes.9-12) Once incorporated into erythrocytes via es-type nucleoside transporter, 13) ribavirin is subjected to intracellular phosphorylation and converted to its phosphorylated metabolites.14) Therefore the concentration of erythrocyte ribavirin including phosphorylated metabolites is 160-fold higher than that in plasma. 9,10) Recent studies have revealed that erythrocyte ribavirin induced intracellular ATP deficiency, leading to downregulation of the hexose monophosphate shunt resulting in accelerated oxidative damage on erythrocyte cell membrane.15) Significant alterations including band 3 aggregation were also found; these are known associated with erythrophagocytosis in reticuloendothelial system (RES).15) Intracellular ATP deficiency may cause ATP-dependent morphological transformation 16) and enzyme activity modification in erythrocytes. It is widely accepted that erythrocytes with ATP deficiency decrease in deformability, which is associated with erythrocyte removal in RES. ATP depletion is known to produce phosphatidylserine (PS) exposure on plasma membrane by inactivation of ATP-dependent aminophospholipid translocase activity.17) Since PS exposure is a key step for phagocytic removal in various cells including thalassemic erythrocytes, 18,19) its association with ribavirin-induced hemolytic anemia may arise.In the present study, we examined morphological transformation and PS exposure in ribavirin-treated erythrocytes invitro in association with intracellular ribavirin accumulation and ribavirin-induced hemolytic anemia. MATERIALS AND METHODS Materials and Reagent SolutionsRibavirin, dipyridamole, and 3-methoxycitidine methosulfate were purchased from Sigma-Aldrich (St. Louis, U.S.A.). Annexin V-fluorescein isothiocyanate conjugate (FITC) Kit was purchased from Immunotech, Beckman-Coulter (Miami, U.S.A.). All other reagents and solvents for assay were of analytical or reagent grade and were purchased from Wako Chemicals (Osaka, Japan) and Sigma-Aldrich.Ribavirin Treatment of Erythrocytes Whole blood was obtained into heparinized tubes from a healthy subject and was centrifuged at 1000ϫg. Erythrocytes were isolated by removing the supernatant, washed 4 times with 3 volumes of PBS and suspended in HEPES-buffered Tyrode solution (137 mM NaCl, 2.7 mM KCl, 12 mM HEPES, 1 mM MgCl 2 , 2 mM CaCl 2 , and 5.6 mM dextrose; pH 7.4) to make the 20% hematocrit preparat...

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Cytopenias: How they Limit Therapy and Potential Correction

Shiffman

2011

Advanced Therapy for Hepatitis C

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Marked elevation of erythrocyte ribavirin levels in interferon and ribavirin-induced anemia

Cited by 52 publications

References 5 publications

Early ribavirin pharmacokinetics, HCV RNA and alanine aminotransferase kinetics in HIV/HCV co-infected patients during treatment with pegylated interferon and ribavirin

Early ribavirin pharmacokinetics, HCV RNA and alanine aminotransferase kinetics in HIV/HCV co-infected patients during treatment with pegylated interferon and ribavirin

Morphological Transformation and Phosphatidylserine Exposure in Erythrocytes Treated with Ribavirin

Cytopenias: How they Limit Therapy and Potential Correction

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