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

Abstract

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 ...

Simultaneous determination of ribavirin and ribavirin base in monkey plasma by high performance liquid chromatography with tandem mass spectrometry

“…have been reported for the determination of ribavirin in biological matrices [24][25][26][27][28][29][30][31][32][33][34]. However, separate methods using HPLC-UV or HPLC with radioactivity detection were used for the measurement of ribavirin base in these samples [22,31,34]. To our best knowledge, only a few HPLC-UV methods are available for the quantification of both ribavirin and ribavirin base in biological samples [35,36].…”

“…The first pathway is a reversible phosphorylation in nucleated cells [10,21,22], and the second is degradation involving deribosylation and/or amide hydrolysis [10,22]. As the result of deribosylation, ribavirin is biotransformed to ribavirin base (1,2,4-triazole-3-carboxamide) [10,22]. In healthy adults, it is estimated that approximately 30-55% of inhalated ribavirin was excreted as ribavirin base in urine within 72-80 h, and about 50% of orally administered ribavirin was excreted as ribavirin base within 24 h [10].…”

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

“…Pharmacokinetic analysis of ribavirin administered to animals indicated that most of the ribavirin is degraded and excreted from urea. Of the remaining drug that is distributed around various parts of the animal, a significant amount exists in the form of triazole nucleobase (3,4). Inhibiting ribavirin phosphorolysis represents a logical strategy to enhance the drug's stability, thereby delivering more active metabolites for efficacy.…”

Virological response and safety outcomes in therapy–naïve patients treated for chronic hepatitis C with taribavirin or ribavirin in combination with pegylated interferon alfa-2a: A randomized, phase 2 study

“…Taribavirin contains a positively charged 3-carboxymide group [12] and is poorly taken up by red blood cells (RBCs). The concentration of taribavirin-derived ribavirin found in RBCs is half that of ribavirin after oral dosing [14]. Higher RBC ribavirin levels correlate with greater decreases in hemoglobin secondary to hemolysis [15], so combination therapy with taribavirin plus pegylated interferon may be associated with a lower incidence of treatment (ribavirin)-related anemia.…”

“…Taribavirin is preferentially taken up by the liver and is likely converted to ribavirin by hepatic adenosine deaminase [13,14]. Taribavirin-derived ribavirin accumulates in the liver at three times the rate of native ribavirin [14].…”