Plasma disappearance, urine excretion, and tissue distribution of ribavirin in rats and rhesus monkeys

Junin virus-infected rhesus macaques received prophylactic and therapeutic ribavirin to assess the potential of this drug for treating humans with Argentine hemorrhagic fever. When ribavirin was administered intramuscularly at the time of experimental infection with the lethal P3790 strain of Junin virus, all animals were protected from clinical disease. A delay in the initiation of therapy until after the onset of illness resulted in improvement and resolution of systemic signs of disease; however, survivors subsequently developed a late-onset central nervous system infection which was fatal in two of three animals. Side effects of ribavirin included thrombocytosis and severe anemia, both of which resolved promptly on withdrawal of drug therapy. Results of this study suggest that ribavirin may prove useful in treating humans with Argentine hemorrhagic fever.

Section: Discussionmentioning

confidence: 99%

“…Objective disease parameters were monitored twice weekly for 5 weeks and then weekly for 4 weeks. These included physical examination, body weight, viremia, virus shedding from the oropharynx, neutralizing antibodies, and hematological indices.…”

Section: Methodsmentioning

confidence: 99%

Ribavirin prophylaxis and therapy for experimental argentine hemorrhagic fever

McKee

Huggins

Trahan

et al. 1988

“…With multiple doses over 3 days, there appeared to be a small accumulation of ribavirin in serum at the end of each day's treatment. Sequestering and clearing of ribavirin from serum would be accomplished by the incorporation of riba-virin triphosphate into erythrocytes (3) and by renal excretion (3,6), respectively. Although we did not measure ribavirin levels in the urine, previous studies in rats have shown that ribavirin is rapidly excreted in the urine (82% is excreted in 24 h) (6).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of ribavirin aerosol in mice

Gilbert

Wyde

1988

The pharmacokinetics of ribavirin administered in single or multiple treatments to mice by small-particle aerosol were monitored in lung, serum, and brain tissues. Ribavirin aerosol was administered with a standard drug concentration (20 mg/ml) in the reservoir for 12 h or a high dose (60 mg/ml) for 2 or 4 h. After single or 3-day treatments, ribavirin rapidly accumulated in the lungs at concentrations sufficient to inhibit influenza virus or respiratory syncytial virus (1 to 5 mM). While peak levels of ribavirin in the lungs after the high-dose administration were about three times those found with the standard dose, ribavirin was rapidly cleared from the lungs. There was no accumulation of drug in the lungs after multiple treatments. Ribavirin cleared from the lungs was detected in the blood within 15 min. Concentrations in the serum were similar (20 to 30 ,IM) for standard-and high-dose treatments with either single or multiple treatments. Ribavirin clearance from the serum after treatment was similar for each regimen. Ribavirin also rapidly accumulated in the brain to a similar level (ca. 6 nmol per brain) after standard-or high-dose treatment for 3 days. In contrast to ribavirin in the serum, ribavirin in the brain appeared to be slowly cleared, allowing levels to remain relatively constant during and after treatment. With the interest in viral encephalopathies, further evaluation of the possible advantages of this method of drug administration is warranted.Ribavirin is a broad-spectrum antiviral agent that is used to treat respiratory syncytial virus infections in infants and has been shown to effectively inhibit the replication of influenza, parainfluenza, and a number of other respiratory viruses (7-10). The current protocol recommends prolonged daily ribavirin treatment periods. of 12 to 18 h. Recently, we showed that a shorter period of treatment with higher concentrations of ribavirin is as effective in reducing pulmonary viral titers in mice and cotton rats (Sigmoden hispidus) experimentally inoculated with influenza or respiratory syncytial virus and in preventing mortality in mice given lethal doses of influenza A or B virus (18,19). In the present study, the pharmacokinetics of ribavirin in lung, serum, and brain tissues of mice given standard and high doses of ribavirin by continuous small-particle aerosol were monitored by using a high-performance liquid chromatography assay (15) to determine drug levels in these tissues during and after administration. Standard administration consisted of 12 h of drug treatment per day with 20 mg of ribavirin per ml in the reservoir. High-dose, short-duration administration consisted of drug treatment for 2 h twice daily with 60 mg of ribavirin per ml in the reservoir.This report shows that after high-dose, short-duration aerosol administration, ribavirin rapidly accumulated in the lungs and was quickly cleared once treatment had ceased; that ribavirin was quickly absorbed into the blood; and that ribavirin appeared to accumulate in brain tissue. MATERIALS AND ...

“…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 […”

mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

Lin¹,

Yeh²,

Luu³

et al. 2003

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...