Effects of ribavirin on red blood cells

Canonico, Peter G.; Kastello, Michael D.; Spears, Charles T.; Brown, James R.; Jackson, Edwin A.; Jenkins, Daniel E.

doi:10.1016/0041-008x(84)90138-8

Cited by 73 publications

(51 citation statements)

References 10 publications

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“…Plasma concentrations of ribavirin reached mean C max values of 1.7-3.2 g/ml over the 14-day dosing period. The time-dependent increase in plasma concentration was likely related to accumulation of ribavirin-TP in red blood cells, leading to an increased half-life of ribavirin in rat plasma (43).…”

Section: Discussionmentioning

confidence: 99%

2′-Deoxy-4′-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2′-α-Hydroxyl Groups

Klumpp

Kalayanov

et al. 2008

Journal of Biological Chemistry

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RNA polymerases effectively discriminate against deoxyribonucleotides and specifically recognize ribonucleotide substrates most likely through direct hydrogen bonding interaction with the 2-␣-hydroxy moieties of ribonucleosides. Therefore, ribonucleoside analogs as inhibitors of viral RNA polymerases have mostly been designed to retain hydrogen bonding potential at this site for optimal inhibitory potency. Here, two novel nucleoside triphosphate analogs are described, which are efficiently incorporated into nascent RNA by the RNA-dependent RNA polymerase NS5B of hepatitis C virus (HCV), causing chain termination, despite the lack of ␣-hydroxy moieties. 2-Deoxy-2-␤-fluoro-4-azidocytidine (RO-0622) and 2-deoxy-2-␤-hydroxy-4-azidocytidine (RO-9187) were excellent substrates for deoxycytidine kinase and were phosphorylated with efficiencies up to 3-fold higher than deoxycytidine. As compared with previous reports on ribonucleosides, higher levels of triphosphate were formed from RO-9187 in primary human hepatocytes, and both compounds were potent inhibitors of HCV virus replication in the replicon system (IC 50 ‫؍‬ 171 ؎ 12 nM and 24 ؎ 3 nM for RO-9187 and RO-0622, respectively; CC 50 >1 mM for both). Both compounds inhibited RNA synthesis by HCV polymerases from either HCV genotypes 1a and 1b or containing S96T or S282T point mutations with similar potencies, suggesting no cross-resistance with either R1479 (4-azidocytidine) or 2-C-methyl nucleosides. Pharmacokinetic studies with RO-9187 in rats and dogs showed that plasma concentrations exceeding HCV replicon IC 50 values 8 -150-fold could be achieved by low dose (10 mg/kg) oral administration. Therefore, 2-␣-deoxy-4-azido nucleosides are a new class of antiviral nucleosides with promising preclinical properties as potential medicines for the treatment of HCV infection. Hepatitis C virus (HCV)3 infection is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma and is the leading cause of liver transplantation. Current treatment options available to HCV-infected persons have limitations with regard to efficacy and tolerability. Only about 50% of individuals infected with HCV genotype 1 achieve sustained virological response when treated with a combination of pegylated interferon ␣ and ribavirin (1, 2). In addition, high viral load, age, body weight, co-infection with human immunodeficiency virus, and cirrhosis negatively affect the probability of achieving sustained virological response (3, 4). Therefore, there is an urgent need to develop new and more effective therapies for the treatment of HCV infection. A number of new antiviral candidates are currently being evaluated in clinical studies, the majority targeting either the HCV protease or HCV polymerase enzymes, which are essential for viral replication (5). The HCV RNA-dependent RNA polymerase, NS5B, contains the active site responsible for viral RNA synthesis and functions as part of a membrane-associated replicase complex. Nucleoside and non-nucleoside inhibitors of HCV polymerase h...

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Section: Discussionmentioning

confidence: 99%

2′-Deoxy-4′-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2′-α-Hydroxyl Groups

Klumpp

Kalayanov

et al. 2008

Journal of Biological Chemistry

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“…The active metabolites of ribavirin, ribavirin 5Ј-mono and 5Ј-triphosphate (RMP and RTP), are formed intracellularly (Russmann et al, 2006); thus, this metabolic activation is in part dependent on the transport of ribavirin into the cell. In addition, these metabolites are polar, and once formed inside the cell, they are unable to diffuse out (Canonico et al, 1984). Ribavirin is transported into human erythrocytes by the human ENT1 (Jarvis et al, 1998).…”

Section: Ribavirinmentioning

confidence: 99%

The Role of Nucleoside Transporters in the Erythrocyte Disposition and Oral Absorption of Ribavirin in the Wild-Type and Equilibrative Nucleoside Transporter 1(−/−) Mice

Endres¹,

Moss²,

Govindarajan³

et al. 2009

J Pharmacol Exp Ther

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Ribavirin [1-(␤-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide] is the treatment of choice for hepatitis C virus infection.Ribavirin is a substrate of several nucleoside transporters, including the equilibrative nucleoside transporter (Ent) and the concentrative nucleoside transporter 2. To determine the role of Ent1 in ribavirin absorption and erythrocyte distribution, we examined its pharmacokinetics in Ent1-null mice. After intravenous administration, we found that the erythrocyte area under the curve (AUC 0 -12 h ) was reduced 3.05-fold along with 2.63-fold reduction of erythrocyte versus plasma AUC ratio in the Ent1(Ϫ/Ϫ) mice, whereas there was no significant difference in the plasma AUC 0 -12 h between Ent1(ϩ/ϩ) and Ent1(Ϫ/Ϫ) mice. After 48 h, we found a similar fraction of ribavirin or total radioactivity excreted in the urine between the Ent1(ϩ/ϩ) and Ent1(Ϫ/Ϫ) mice. After oral administration of three different doses, 0.024, 0.24, and 6.1 mg/kg, we found that the dosenormalized plasma AUC 0 -12 h of ribavirin was 69.7 Ϯ 12.0, 20.7 Ϯ 1.5, and 18.3 Ϯ 2.7 min/l, respectively, in the Ent1(ϩ/ϩ) mice and 18.9 Ϯ 2.8, 13.0 Ϯ 0.5, and 12.2 Ϯ 1.0 min/l, respectively, in the Ent1(Ϫ/Ϫ) mice. It is interesting that at the highest dose, the dose-normalized plasma AUC 0 -30 min , AUC 0 -12 h , and C max in the Ent1(ϩ/ϩ) mice were decreased 4.0-, 3.8-, and 3.4-fold, respectively, compared with the lowest dose, suggesting absorption was saturated at the highest dose we used. The dose-normalized plasma AUC 0 -12 h was 3.7-and 1.5-fold lower at the lowest and the highest dose, respectively, in the Ent1(Ϫ/Ϫ) mice compared with those of the Ent1(ϩ/ϩ) mice. Our findings indicate that Ent1 plays a significant role in the oral absorption and erythrocyte distribution of ribavirin. Ribavirin[1-(␤-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide], with polyethylene glycol-conjugated interferon-␣, is currently the standard of treatment for chronic hepatitis C virus infection. Worldwide, approximately 200 million people (of which 3.2 million are in the United States) are chronically infected with the hepatitis C virus (Sherlock, 1995;Armstrong et al., 2006). Even at its usual recommended dose, treatment with ribavirin is limited by its major toxicity, hemolytic anemia (Fried, 2002). In 10 to 13% of patients, this anemia is profound enough to result in either dose reduction or discontinuation of therapy (Fried, 2002), leading to lack of effective treatment of the infection. Ribavirin is a prodrug and exhibits its broad antiviral activity through its active phosphorylated metabolites (Parker, 2005). There is mounting evidence that the hematological toxicity of ribavirin is due to the significant accumulation and lack of dephosphorylation of the active phosphorylated metabolites in the erythrocytes (Parker, 2005). Multiple studies have observed significant correlations between the intracellular ribavirin concentration and the magnitude of hemolytic anemia observed clinically (Homma et al., 2004;Inoue et al., 2006).Because ri...

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“…These data suggest that the total ribavirin-related components may account for most of the drug in the monkey liver following prolonged administration of viramidine. Canonico et al (1) reported that monkey RBC accumulated the largest concentration of ribavirin, followed by human and rat RBC. Ribavirin is transported by the nitrobenzylthioinosine-sensitive nucleoside transporter into human RBC (5).…”

mentioning

confidence: 99%

Disposition and Metabolic Profiles of [ ¹⁴ C]Viramidine and [ ¹⁴ C]Ribavirin in Rat and Monkey Red Blood Cells and Liver

Lin

Lourenco

et al. 2004

Antimicrob Agents Chemother

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The disposition and metabolic profiles of [14 C]viramidine and [ 14 C]ribavirin were compared in rat and monkey red blood cells and liver. Our data reveal that the total ribavirin-related components (ribavirin plus its mono-, di-, and triphosphate metabolites) may account for most of the drug in monkey liver following prolonged oral administration of viramidine.Ribavirin is a purine nucleoside analog ( Fig. 1) with broadspectrum activity against a variety of DNA and RNA viral infections (17,19). In combination with either alpha interferon or pegylated alpha interferon, the clinical efficacy of ribavirin in the treatment of chronic hepatitis C virus infection, in terms of a sustained virologic response, has been shown to be about 41 to 47% (13, 16) and 54 to 56% (4, 11, 12), respectively. However, ribavirin had a dose-limiting side effect. After entering the circulation, a significant portion of ribavirin is transported into erythrocytes (RBC) (6) and metabolized into various phosphorylated derivatives (15). Owing to the lack of phosphatase activity in RBC, these phosphorylated metabolites of ribavirin are trapped intracellularly and accumulate over time, leading to hemolytic anemia (6,7,15). This adverse effect often necessitates dose reduction and discontinuation of ribavirin therapy in a significant proportion of patients. Therefore, a new form of ribavirin that retains ribavirin's clinical efficacy but has less potential for hemolytic anemia would be highly desirable.Viramidine ( Fig. 1) may be converted to ribavirin by adenosine deaminase (21). In rats and monkeys following oral administration, viramidine was extensively converted to ribavirin, followed by further metabolism to ribofuranosyl triazole carboxylic acid and triazole carboxamide (TCONH 2 ) (8). Ribavirin has also been reported to undergo metabolism to ribofuranosyl triazole carboxylic acid and TCONH 2 (9). Despite the lower absorption of viramidine compared to that of ribavirin, the plasma ribavirin AUC after viramidine administration in rats was similar to or slightly higher than the plasma ribavirin AUC after ribavirin administration (8,9). This is in good agreement with the rapid conversion of viramidine to ribavirin in rats. In monkeys, however, the plasma ribavirin AUC following viramidine administration was lower than the plasma ribavirin AUC following ribavirin administration. This is probably related to either lower absorption of viramidine compared to that of ribavirin in monkeys and/or the slower rate of conversion of viramidine to ribavirin (8, 9). [ 14 C]viramidine administration in rats produced a 32% higher liver radioactivity AUC than did [14 C]ribavirin administration (10). Cynomolgus monkeys with portal vein cannulas that were given [ 3 H]viramidine retained three times the liver radioactivity of those given [ 3 H]ribavirin (10). However, no metabolic profile in rat and monkey liver has been evaluated. The aim of this study was to compare the disposition and metabolic profiles of viramidine and ribavirin in the RBC and livers of ...

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Effects of ribavirin on red blood cells

Cited by 73 publications

References 10 publications

2′-Deoxy-4′-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2′-α-Hydroxyl Groups

2′-Deoxy-4′-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2′-α-Hydroxyl Groups

The Role of Nucleoside Transporters in the Erythrocyte Disposition and Oral Absorption of Ribavirin in the Wild-Type and Equilibrative Nucleoside Transporter 1(−/−) Mice

Disposition and Metabolic Profiles of [ ¹⁴ C]Viramidine and [ ¹⁴ C]Ribavirin in Rat and Monkey Red Blood Cells and Liver

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Effects of ribavirin on red blood cells

Cited by 73 publications

References 10 publications

2′-Deoxy-4′-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2′-α-Hydroxyl Groups

2′-Deoxy-4′-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2′-α-Hydroxyl Groups

The Role of Nucleoside Transporters in the Erythrocyte Disposition and Oral Absorption of Ribavirin in the Wild-Type and Equilibrative Nucleoside Transporter 1(−/−) Mice

Disposition and Metabolic Profiles of [ 14 C]Viramidine and [ 14 C]Ribavirin in Rat and Monkey Red Blood Cells and Liver

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Disposition and Metabolic Profiles of [ ¹⁴ C]Viramidine and [ ¹⁴ C]Ribavirin in Rat and Monkey Red Blood Cells and Liver