Dual-Action Mechanism of Viramidine Functioning as a Prodrug and as a Catabolic Inhibitor for Ribavirin

Wu, Jim Zhen; Larson, Gary; Hong, Zhi

doi:10.1128/aac.48.10.4006-4008.2004

Cited by 21 publications

(8 citation statements)

References 10 publications

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“…However, in rats, the drug targeting was less pronounced, consistent with the observation that viramidine (228) provides a better safety profile in monkeys than rats [855]. In addition to acting as a prodrug of ribavirin (229), viramidine (228) also appears to interfere with nucleoside phosphorylase-mediated deglycosylation of ribavirin (229), thereby inhibiting catabolism of the metabolite [856].…”

Section: Rivbavirin and Viramidinesupporting

confidence: 69%

Developments in Antiviral Drug Design, Discovery and Development in 2004

Meanwell

Belema²,

Carini³

et al. 2005

CDTID

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This article summarizes key aspects of progress made during 2004 toward the design, discovery and development of antiviral agents for clinical use. Important developments in the identification, characterization and clinical utility of inhibitors of human immunodeficiency virus; the hepatitis viruses, hepatitis B, hepatitis C; the herpes family of viruses, herpes simplex viruses 1 and 2, varicella zoster virus, Epstein-Barr virus and human cytomegalovirus; the respiratory viruses, influenza, respiratory syncytial virus, human metapneumovirus, picornaviruses, measles and the severe acute respiratory syndrome coronavirus; human papilloma virus; rotavirus; Ebola virus and West Nile virus, are reviewed.

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Section: Rivbavirin and Viramidinesupporting

confidence: 69%

Developments in Antiviral Drug Design, Discovery and Development in 2004

Meanwell

Belema²,

Carini³

et al. 2005

CDTID

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“…Pharmacokinetic analysis indicates that this prodrug is capable of delivering more ribavirin to the liver with a reduced propensity to be trapped in RBCs (20,38). In addition to the prodrug mechanism, viramidine may concurrently act as a catabolic inhibitor and slow down the catabolic rate of newly converted ribavirin from viramidine (37). Because of these favorable pharmacokinetic properties, viramidine is currently in clinical trials for the treatment of chronic HCV infection.…”

mentioning

confidence: 99%

Phosphorylation of Ribavirin and Viramidine by Adenosine Kinase and Cytosolic 5′-Nucleotidase II: Implications for Ribavirin Metabolism in Erythrocytes

Larson

Walker

et al. 2005

Antimicrob Agents Chemother

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Many nucleoside analog drugs, such as ribavirin and viramidine, are activated or metabolized in vivo through 5-phosphorylation. In this report, we determined the steady-state kinetic parameters for 5-monophosphorylation of ribavirin and viramidine by adenosine kinase. The apparent K m for ribavirin is 540 M, and k cat is 1.8 min ؊1 . Its catalytic efficiency of 3.3 ؋ 10 ؊3 min ؊1 · M ؊1 is 1,200-fold lower than that of adenosine. In contrast to the common belief that ribavirin is exclusively phosphorylated by adenosine kinase, cytosolic 5-nucleotidase II was found to catalyze ribavirin phosphorylation in vitro. The reaction is optimally stimulated by the physiological concentration of ATP or 2,3-bisphosphoglycerate. In phosphate-buffered saline plus ATP and 2,3-bisphosphoglycerate, the apparent K m for ribavirin is 88 M, and k cat is 4.0 min ؊1 . These findings suggest that cytosolic 5-nucleotidase II may be involved in ribavirin phosphorylation in vivo. Like ribavirin, viramidine was found to be phosphorylated by either adenosine kinase or cytosolic 5-nucleotidase II, albeit with a much lower activity. The catalytic efficiency for viramidine phosphorylation is 10-to 330-fold lower than that of ribavirin, suggesting that other nucleoside kinase(s) may be involved in viramidine phosphorylation in vivo. Both ribavirin and viramidine are not phosphorylated by deoxycytidine kinase and uridine-cytidine kinase. The coincidence of presence of high concentrated 2,3-bisphosphoglycerate in erythrocytes suggests that cytosolic 5-nucleotidase II could play an important role in phosphorylating ribavirin and contribute to anabolism of ribavirin triphosphate in erythrocytes. Elucidation of ribavirin and viramidine phosphorylation mechanism should shed light on their in vivo metabolism, especially the ribavirin-induced hemolytic anemia in erythrocytes.

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“…Its biological activity observed in cell culture and in vivo animal models is likely derived from ribavirin generated by a prodrug mechanism (Wu et al, 2003a;Wu et al, 2003b). In addition, viramidine may serve as a catabolic inhibitor for ribavirin and prevent ribavirin from phosphorolysis by inhibiting purine nucleoside phosphorylase ( Figure 1) (Wu et al, 2004). More importantly, viramidine exhibits a more desirable drug tissue distribution profile than ribavirin.…”

confidence: 99%

“…This disparity may be interpreted by our previous observation that viramidine is able to inhibit ribavirin catabolism and stabilize the newly synthesized ribavirin. As reported, viramidine is a potent inhibitor for purine nucleoside phosphorylase, the enzyme that degrades ribavirin (Wu et al, 2004;Willis et al, 1980). As illustrated in Figure 1, a higher concentration of viramidine in rat plasma as a result of ADA inhibition by 2′-dCF may prevent more ribavirin from catabolism, resulting in a higher concentration of ribavirin.…”

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confidence: 91%

Conversion of Viramidine to Ribavirin in Vivo by Adenosine Deaminase and its Inhibition by 2′-Deoxycoformycin

Yeh

Lin

et al. 2006

Antivir Chem Chemother

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Previously we reported that viramidine is a prodrug of ribavirin and that adenosine deaminase catalyses viramidine deamination to ribavirin in vivo. This in vivo study explores this prodrug conversion in rats and inhibition by a potent adenosine deaminase inhibitor, 2'-deoxycoformycin. We found that conversion of viramidine to ribavirin was viramidine dose-dependent in rat plasma. A single intravenous dose of 0.25 mg/kg 2'-deoxycoformycin suppressed orally administered viramidine conversion to ribavirin in plasma by 50%. The inhibition was 2'-deoxycoformycin dose-dependent and a single dose of 2 mg/kg decreased the ribavirin/viramidine area under the concentration-time curve between 0 h and 6 h ratio by 2.5-fold. These findings provide strong evidence that adenosine deaminase plays a major role in converting viramidine to ribavirin in vivo.

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Dual-Action Mechanism of Viramidine Functioning as a Prodrug and as a Catabolic Inhibitor for Ribavirin

Cited by 21 publications

References 10 publications

Developments in Antiviral Drug Design, Discovery and Development in 2004

Developments in Antiviral Drug Design, Discovery and Development in 2004

Phosphorylation of Ribavirin and Viramidine by Adenosine Kinase and Cytosolic 5′-Nucleotidase II: Implications for Ribavirin Metabolism in Erythrocytes

Conversion of Viramidine to Ribavirin in Vivo by Adenosine Deaminase and its Inhibition by 2′-Deoxycoformycin

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