Pharmacokinetics and Metabolism of [¹⁴C]Ribavirin in Rats and Cynomolgus Monkeys

Abstract

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...

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

“…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 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).…”

“…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 RBC samples were solubilized with Solvable (Packard Instruments) and then decolorized with hydrogen peroxide. The mixtures were then neutralized with 0.5 N hydrochloric acid and measured for radioactivity by liquid scintillation counting.…”

Efeitos colaterais do uso da ribavirina, prednisona e DMSO em cães naturalmente infectados pelo vírus da cinomose

“…O acúmulo dos fosfatos do antiviral em eritrócitos leva a anemia (Wu et al 2005). A severidade da anemia é mais grave em macacos, seguidos dos humanos, roedores e cães (Lin et al 2003).…”

“…Os metabólitos fosforilados diminuem os níveis de ATP intracelular, resultando na perda da integridade dos eritrócitos por desestabilização da membrana que pode causar hemólise extravascular (Inoue et al 2004, Hitomi et al 2011. A severidade da anemia é mais grave em macacos, a seguir em humanos, roedores e cães (Lin et al 2003). Ela ocorre em 30% dos casos tratados e resulta em 9% a 22% de pacientes que necessitam a redução da dose para continuar o tratamento.…”