The pharmacokinetics of [14 C]viramidine, a prodrug of ribavirin, were studied in rats (30 mg/kg of body weight) and monkeys (10 mg/kg) following intravenous (i.v.) and oral administration. The levels of oral absorption and bioavailabilities were 61.7 and 9.91%, respectively, in rats and 43.9 and 13.6%, respectively, in monkeys. Following i.v. administration, the elimination half-lives were 2.7 h in rats and 28.9 h in monkeys. Total body clearances were 14.0 liters/h/kg in rats and 1.23 liters/h/kg in monkeys; the apparent volumes of distribution were 15.6 liters/kg in rats and 18.6 liters/kg in monkeys. Following oral administration, viramidine was extensively converted to ribavirin, followed by further metabolism of ribavirin in both species, with a faster rate of metabolism in rats than in monkeys. In rats, excretion of total radioactivity in urine accounted for 77.0% of the i.v. dose and 60.8% of the oral dose, while in monkeys it accounted for 44.4% of the i.v. dose and 39.0% of the oral dose. The amount of unchanged viramidine and ribavirin in urine was small in both species after i.v. and oral administration of viramidine.Ribavirin (1-␤-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a purine nucleoside analog with activity against a variety of DNA and RNA viral infections (10, 11). The clinical efficacies of interferon alfa-2b and pegylated interferon alfa-2b in combination with ribavirin are about 40% (6, 9) and 54% (5), respectively, in terms of a sustained virologic response when they are used to treat chronic hepatitis C virus infection. At present, combination therapy with ribavirin and pegylated interferon alfa-2b is the "gold standard" for the treatment of chronic hepatitis C. However, ribavirin has a dose-limiting side effect, hemolytic anemia. After absorption into the circulation, a significant portion of ribavirin is transported into red blood cells (RBCs) (2) and phosphorylated into the triphosphate form (8). Due to the lack of phosphatase activity in erythrocytes, phosphorylated derivatives of ribavirin are retained intracellularly and accumulate over time, leading to hemolytic anemia (1, 3). This side effect is dose limiting and necessitates dose reduction and withdrawal in some patients. A new ribavirin which retains those properties deemed critical in the treatment of chronic hepatitis C, but with less potential for hemolytic anemia, would be highly desirable.Viramidine is a prodrug of ribavirin. Preliminary studies in our laboratories indicated that viramidine can be retained and converted to ribavirin in the liver (J. AASLD, abstr. 1123AASLD, abstr. , 2001. Since the liver is the target for hepatitis C virus infection and since RBCs are the target for ribavirin toxicity, the use of viramidine may provide an opportunity to improve the efficacy and reduce the toxicity associated with ribavirin.The aim of this study was to determine the absorption, pharmacokinetics, metabolism, and excretion of viramidine in rats and monkeys. MATERIALS AND METHODS Compound. The compound [5-14 C]virami...

Absorption, pharmacokinetics, distribution, metabolism, and excretion of [ 14 C]ribavirin were studied in rats (30 mg/kg of body weight) and cynomolgus monkeys (10 mg/kg) after intravenous (i.v.) and oral administration. The oral absorption and bioavailability were 83 and 59%, respectively, in rats and 87 and 55%, respectively, in monkeys. After i.v. administration, the elimination half-life (t [1/2] ) was 9.9 h in rats and 130 h in monkeys and the total body clearance was 2,600 ml/h/kg in rats and 224 ml/h/kg in monkeys. The apparent volume of distribution was 11.4 liter/kg in rats and 29.4 liter/kg in monkeys. There was extensive distribution of drug-derived radioactivity into red blood cells and extensive metabolism of ribavirin in rats and a lesser degree of metabolism in monkeys. Excretion of total radioactivity in urine from rats accounted for 84% of the i.v. dose and 83% of the oral dose, whereas that from monkeys accounted for 47% of the i.v. dose and 67% of the oral dose. Several metabolites were observed in plasma and urine from both species. The amount of unchanged ribavirin in urine from both species was quite small after either i.v. or oral administration.is a purine nucleoside analog with broad-spectrum activity against a variety of DNA and RNA viral infections (6,8). In combination with alpha interferon (IFN-␣), the clinical efficacy of this drug in the treatment of chronic hepatitis C virus infection has been shown by many studies. The in vivo activity of ribavirin can be ascribed to at least two distinct groups of activities, namely, direct and indirect antiviral effects (13). The direct antiviral effect of ribavirin is attributed to its intracellular metabolites, including the mono-, di-, and triphosphorylated forms of ribavirin (7). Ribavirin may also elicit indirect antiviral effects by promoting T-cell-mediated immunity or by affecting the intracellular GTP concentration through inhibition of the host enzyme IMP dehydrogenase (IMPDH), thereby depleting the intracellular GTP pool available for viral replication (9-12).Red blood cell and plasma levels of radioactivity and recovery of urinary radioactivity after intravenous (i.v.) and intramuscular (i.m.) dosing of [ 14 C]ribavirin have been studied in rats (1, 2). A similar study was also conducted with rhesus monkeys after i.v. dosing of [ 14 C]ribavirin (2). However, no oral dosing studies based on [ 14 C]ribavirin have been conducted. Miller et al. (4) reported the distribution of radioactivity and composition of metabolites in serum, urine, and various tissues in rats after i.v. and oral dosing of [ 3 H]ribavirin. However, concentrations of ribavirin were not determined in these studies and no pharmacokinetic parameters were reported. Thus, the absorption and bioavailability and various pharmacokinetic parameters of ribavirin after oral administration have not been evaluated in animal studies.The objectives of this study were to determine the absorption, bioavailability, pharmacokinetics, distribution, metabolism, and excretion of ribavir...

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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 ...

Single-dose pharmacokinetics and metabolism of [14 C]remofovir was studied in rats and monkeys following intravenous (i.v.) and oral administration (30 mg/kg of body weight). Oral absorption and bioavailability were 29.7 and 5.42% in rats and 65.6 and 19.4% in monkeys, respectively. Following i.v. administration, the elimination half-life for remofovir was 0.7 h in both rats and monkeys. Total body clearance was 5.85 liters/h/kg in rats and 2.60 liters/h/kg in monkeys; apparent volume of distribution was 5.99 liters/kg in rats and 2.70 liters/kg in monkeys. Following oral administration, remofovir was extensively converted to 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and other metabolites in both species. In rats, excretion of total radioactivity in urine accounted for 61.8% of the i.v. dose and 12.9% of the oral dose, while in monkeys it accounted for 43.3% of the i.v. dose and 34.9% of the oral dose. Following i.v. dosing of [ 14 C]remofovir, fecal excretion of radioactivity accounted for 37.5% of the dose in rats and 17.4% of the dose in monkeys, indicating significant biliary excretion of the drug in animals. PMEA and metabolite A were the major urinary metabolites in both species after i.v. and oral administration of remofovir.Adefovir, 9-(2-phosphonylmethoxyethyl)adenine (or PMEA), is an acyclic phosphonate analogue of adenine which has been shown to be effective against hepatitis B virus (HBV) in stably transfected human hepatocellular carcinoma cell lines and primary duck hepatocytes infected with duck HBV and in the duck model of hepatitis B (5, 6). PMEA is phosphorylated to PMEA diphosphate by cellular kinases which inhibit HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate dATP and by causing DNA chain termination after its incorporation into viral DNA (9). Cerny et al.(1) reported that PMEA was converted to four metabolites, including PMEA monophosphate and PMEA diphosphate. However, PMEA is poorly absorbed in a number of species, including rats, monkeys, and humans (2, 3, 11). The low oral bioavailability of PMEA appears to be in part a consequence of the limited intestinal permeability of phosphonate, which is ionized at a physiological pH (10).Adefovir dipivoxil is an oral prodrug of PMEA. In clinical trials, at week 48, serum HBV DNA levels had decreased by a median of 3.52 log copies per ml in the group given 10 mg of adefovir dipivoxil and 4.76 log copies per ml in the 30-mg group, compared with 0.55 log copies per ml in the placebo group (P Ͻ 0.001 for each comparison). Twenty-one percent of the patients in the 10-mg group and 39% of those in the 30-mg group had undetectable serum levels of HBV DNA, compared with 0% of the patients in the placebo group (P Ͻ 0.001 for each comparison) (8). It is clear that 30 mg of adefovir dipivoxil had better efficacy than 10 mg of the drug. However, dose-limiting kidney toxicity was an undesired side effect for adefovir dipivoxil. The incidence of serum creatinine increase (0.3 to Ͻ0.5 mg/dl from baseline) was significantly h...