Testing Information

Testing Status of Agents at NTP

CAS Registry Number: 36791-04-5 Toxicity Effects

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Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 1

Names (NTP)

  • Ribavirin
  • 1H-1,2,4-TRIAZOLE-3-CARBOXAMIDE,1-BETA-D-RIBOFURANOSYL (9CI)

Human Toxicity Excerpts

  • SIGNS AND SYMPTOMS: Rash, erythema of the eyelids, and conjunctivitis have occurred in patients receiving ribavirin inhalation therapy. These effects usually resolve within hours after ribavirin therapy is discontinued. In addition, hearing disorders (e.g., hearing loss, tinnitus), vertigo, hypertriglyceridemia, and fatal and nonfatal pancreatitis have been observed in patients receiving ribavirin in conjunction with interferon alfa-2b. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 806]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Coadministration /of didanosine/ with oral ribavirin is not recommended; cases of fatal hepatic failure, peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials. [Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 2585]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Worsening of respiratory function has occurred, sometimes suddenly, during ribavirin inhalation therapy in infants with RSV infections or in adults with chronic obstructive pulmonary disease (COPD) or asthma. In infants with underlying life-threatening conditions, inhalation of the drug has been associated with aggravation and worsening of respiratory function, apnea, and physical dependence on assisted respiration. In adults with COPD or asthma, therapy with the drug frequently has been associated with deterioration in pulmonary function, and dyspnea and chest soreness have occurred in several adults with asthma. Minor pulmonary function abnormalities have also been observed in healthy adults receiving ribavirin inhalation. Bronchospasm, pulmonary edema, hypoventilation, cyanosis, dyspnea, bacterial pneumonia, pneumothorax, apnea, atelectasis, and ventilator dependence also have been associated with ribavirin inhalation therapy. Several deaths that were characterized as possibly related to ribavirin inhalation therapy by the treating physician occurred in infants who experienced worsening respiratory status related to bronchospasm while receiving the drug. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 805]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Ribavirin inhalation therapy in patients who require assisted respiration has resulted in mechanical problems caused by precipitation of the drug in the respiratory apparatus, including the endotracheal tube and other tubing, and may result in inadequate assisted respiration and gas exchange in these patients. Increases in positive inspiratory and end-expiratory pressures have occurred in these patients as a result of drug precipitation and subsequent malfunction or obstruction of valves in the respiratory apparatus, and pneumothorax can result from such alterations in the pressures of the apparatus. Accumulation of fluid in tubing of the apparatus ("rain out") has also occurred. There have been several deaths reported in infants with RSV who were undergoing assisted respiration while receiving ribavirin inhalation therapy. In these cases, death was attributed to mechanical ventilator malfunction caused by precipitation of the drug within the ventilator apparatus that led to excessively high pulmonary pressures and diminished oxygenation. Whenever ribavirin inhalation therapy is used in a patient requiring mechanical ventilator assistance, strict attention must be paid to procedures that have been shown to minimize the accumulation of drug precipitate. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 805]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: The most frequent adverse effects reported to date in health-care personnel exposed to aerosolized ribavirin include eye irritation (which may be more likely in contact lens wearers) and headache, which usually were mild and reversible following discontinuance of exposure. Nasal and/or throat irritation, pharyngitis, lacrimation, nausea, dizziness, fatigue, rash, bronchospasm, chest pain, and nasal congestion also have been reported in health-care personnel in contact with patients undergoing ribavirin inhalation therapy. A causal relationship between many of these adverse effects and ribavirin exposure has not been established. In most cases, these adverse effects resolved within minutes to hours of discontinuing close exposure to aerosolized ribavirin and few of the personnel exposed to aerosolized drug required medical attention. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 806]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: The primary toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin. [Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 3083]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by Ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued. [Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 3085]**PEER REVIEWED**
  • CASE REPORTS: Ribavirin is a synthetic guanosine analog with activity against DNA and RNA viruses. It was studied in human trials, and no marked adverse effect was reported beyond the potential for teratogenicity and reversible mild anemia. An 8-year-old girl received a multivisceral transplant and developed adenoviral pneumonia. She was treated with intravenous ribavirin and became hyperammonemic. Discontinuation of ribavirin led to a decrease in ammonia levels. This pattern was repeated when the drug was restarted and discontinued. We hypothesize that in a toxic environment the interaction of ribavirin with hepatocellular mitochondrial enzymes may lead to hyperammonemia. [Bertrand P et al; Pharmacotherapy 20 (10): 1216-20 (2000) ]**PEER REVIEWED** PubMed Abstract

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Non-Human Toxicity Excerpts

  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Cardiac lesions were observed in mice and rats receiving ribavirin inhalation dosages of 30 and 36 mg/kg daily, respectively, for 4 wk, and in monkeys and rats receiving oral dosages of 120 and 154-200 mg/kg daily, respectively, for 1-6 mon. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 805]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Results of a chronic feeding study in rats receiving 16-100 mg/kg daily (estimated human equivalent of 2.3-14.3 mg/kg daily based on body surface area adjustment for the adult) suggest that ribavirin may induce benign mammary, pancreatic, pituitary, and adrenal tumors. Preliminary results of 2 oral gavage oncogenicity studies in mice and rats receiving 18-24 months of ribavirin are inconclusive as to the carcinogenic potential of the drug but demonstrate a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages) in mice and retinal degeneration in rats. The mice and rats in these studies received 20-75 and 10-40 mg/kg, respectively, of ribavirin daily (estimated human equivalent of 1.67-6.25 and 1.43-5.71 mg/kg, respectively, daily based on body surface area adjustment for the adult). [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 808]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Ribavirin has been shown to produce testicular lesions (e.g., tubular atrophy) in adult rats receiving oral dosages of 16 mg/kg daily (estimated human equivalent of 2.29 mg/kg daily based on body surface area adjustment for the adult); lower dosages were not tested. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 808]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In studies in mice, ribavirin dosages of 35-150 mg/kg daily (estimated human equivalent of 2.92-12.5 mg/kg daily based on body surface area adjustment for the adult) resulted in seminiferous tubule atrophy, decreased sperm concentrations, and increased numbers of sperm with abnormal morphology; partial recovery of sperm production was apparent 3-6 months after the drug was discontinued. ... In addition, sperm abnormalities have occurred in mice following oral ribavirin doses of 15-150 mg/kg daily (estimated human equivalent of 1.25-12.5 mg/kg/day, based on body surface area adjustment for a 60-kg adult; 0.1-0.8 times the maximum human 24-hour dose of ribavirin) administered for 3 or 6 months. Essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenesis cycles following discontinuance of the drug. However, ribavirin is known to accumulate in intracellular components of cells from which the drug is cleared very slowly, and it is not yet known whether ribavirin contained in sperm will exert a potential teratogenic effect upon fertilization of the ova. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 808]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Evidence of teratogenicity was observed following a single oral ribavirin dose of 2.5 mg/kg in hamsters and following oral dosages of 10 mg/kg daily in rats. Abnormalities of the skull, brain, skin, palate, eye, jaw, skeleton, and GI tract were observed in rats receiving oral ribavirin dosages of 10, 30, 60, or 90 mg/kg daily on days 6-15 of gestation and in hamsters receiving oral and/or parenteral dosages of 2.5-5 or 25 mg/kg on days 7-9 or 12-15 of gestation, respectively. Reproduction studies in rats using oral ribavirin dosages of 60 and 90 mg/kg daily have shown decreases in the number of live births and in fetal survival (first and second generation). Reproduction studies in hamsters using an IV ribavirin dose of 5 mg/kg on day 8 of gestation have shown an increased rate of resorption. Ribavirin has been shown to produce skeletal malformations in rabbits receiving oral dosages of 0.3 mg/kg daily and was embryocidal in rabbits receiving oral dosages of 1 mg/kg daily. When administered orally in dosages of 120 mg/kg daily in baboons, however, ribavirin showed no evidence of teratogenic or embryocidal effects. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 808]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: The present study was planned to evaluate the toxic effects of ribavirin on the reproductive parameters in the male Wistar rat. Rats (11-13 weeks old) were treated with 5 injections (i.p.) of 20, 100 or 200 mg/kg/day ribavirin at intervals of 24 hr. The testes were processed for histopathological analysis on days 14, 35, 70 and 105 after the last exposure. The parameters studied were body weight, the weights of the testis, epididymis, seminal vesicle and prostate, seminiferous tubular diameter (STD), epithelial height (SE), epithelial sloughing, incidence of stage XIV tubules, sperm abnormality and total serum level of testosterone. Data were analysed by ANOVA and the Bonferroni post hoc test for significances between different groups. There was a decrease in body weight and organ weights, excluding those of the testis and epididymis, against control at higher dose-levels. Ribavirin induced the formation of vacuoles, gaps and sloughing of the seminiferous epithelium. The STD, SE and the incidences of stage XIV tubules decreased on days 14 and 35. Ribavirin also induced the formation of sperm with microcephaly and cephalocaudal junction defects, with or without fibrils jetting out. All these morphological defects recovered to control limit by day 105. The serum level of testosterone was decreased at all dose-levels and time points, although recovery had started by day 105. In conclusion, ribavirin is gonadotoxic in male rats but the effects are reversible after a period of 105 days. However, the endocrine-disrupting properties of ribavirin persist beyond this period. [Narayana K et al; Folia Morphol (Warsz) 64 (2): 65-71 (2005) ]**PEER REVIEWED** PubMed Abstract
  • GENOTOXICITY: Ribavirin increased the incidence of cell transformations and mutations in mouse Balb/c 3T3 fibroblasts at concentrations of 0.015 mg/mL and in L5178Y lymphoma cells at concentrations of 0.03-5 mg/mL (without metabolic activation). In vitro, in L5178Y cells with the addition of a metabolic activation fraction, there were modest increases in mutation rates (3-4 times higher) at ribavirin concentrations of 3.75-10 mg/mL. In the mouse micronucleus assay, ribavirin was clastogenic at IV doses of 20-200 mg/kg (estimated human equivalent of 1.67-16.7 mg/kg based on body surface area adjustment for a 60-kg adult); however, the drug was not mutagenic in a dominant lethal assay in rats at intraperitoneal doses of 50-200 mg/kg administered for 5 days (estimated human equivalent of 7.14-28.6 mg/kg based on body surface area adjustment for the adult). [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 807]**PEER REVIEWED**
  • GENOTOXICITY: In this study, we investigated the in vivo genotoxicity of ribavirin in humans, studying 3 patients with Crimean-Congo hemorrhagic fever who were treated with high-dose ribavirin. In order to evaluate genotoxicity, both the micronucleus (MN) test and the sister chromatid exchange (SCE) test were used. In all patients, blood samples were taken during and after therapy. Whole blood cultures were performed for 72 h and the MN assay and SCE test were then carried out to demonstrate the genotoxicity. In all patients, both SCE and MN amounts were found to be higher in the samples which were taken during therapy than in those at 1 month after therapy. The results of our study reveal that ribavirin has a reversible in vivo genotoxic effect on humans. [Tatar A et al; Jpn J Infect Dis 58 (5): 313-5 (2005) ]**PEER REVIEWED** PubMed Abstract
  • GENOTOXICITY: The genotoxic and cytotoxic effects of the antiviral drug, ribavirin, was studied in rat bone marrow by employing the micronucleus assay. Ribavirin in doses of 10, 15, 20, 30, 50, 75, 100 and 200 mg/kg, and cyclophosphamide (CP) 40 mg/kg (only for sex-difference study) were injected intraperitoneally. Bone marrow was collected at 24 h and 48 h following the injection. To evaluate the recovery, the bone marrow was also sampled at 72 h from 20, 100 and 200 mg/kg treated rats. The micronucleus assay was conducted according to the standard procedure. Ribavirin elevated the incidence of micronuclei (except 10 mg/kg) in erythrocytes (P<0.01). The micronucleated polychromatic erythrocytes showed the initial steep increase at 15 and 20 mg/kg dose level, then with the gradual increase, possibly due to the limited metabolism and action of higher doses. The incidence of micronucleated normochromatic erythrocytes was not dose dependent. The effect was more at 48 h than 24 h due to prolonged toxicity of the drug or its metabolites, and by 72 h, recovery was observed even though the genotoxicity was significant. The PCE% decreased as the dose was increased up to 75 mg/kg, then without much difference between two higher doses. Only 100 mg/kg ribavirin and CP showed more toxicity on male rats. Cytotoxicity was seen due to hindered erythropoiesis or cell destruction. Our findings suggest that ribavirin is genotoxic and cytotoxic agent for rat bone marrow. [Narayana K et al; Mutat Res 521 (1-2): 179-85 (2002) ]**PEER REVIEWED** PubMed Abstract
  • GENOTOXICITY: Ribavirin (1-beta-D-ribofuranosyl-1,2,4, triazole-3 carboxamide) is a broad-spectrum antiviral drug. This study was aimed to investigate the mutagenicity of ribavirin on germ cells by employing sperm morphology assay. Male Wistar rats were treated with water, cyclophosphamide (CP) 40 mg/kg, and ribavirin 20, 100 and 200 mg/kg (i.p.) for 5 consecutive days at intervals of 24hr. Following the last exposure, at 14, 28, 35, 42 and 70 days, the epididymal sperm smears were obtained and stained according to the standard procedure. One thousand sperms per animal were classified into normal and different abnormal types. Both CP and ribavirin-induced anomalies of head and tail of sperm except at 70 days. In CP groups, maximum incidence was observed at 28, 35 and 42 days. Ribavirin 20 mg/kg induced maximum incidence at 14 and 42 days, 100 mg/kg at 28 and 42 days and 200 mg/kg at 28-42 days. These results show that ribavirin is mutagenic to rat germ cells in a transient fashion. [Narayana K et al; Mutat Res 513 (1-2): 193-6 (2002) ]**PEER REVIEWED** PubMed Abstract
  • GENOTOXICITY: The micronucleus test and mitotic chromosome analysis were used to study the in vivo mutagenic activity of ribavirin on bone marrow cells of Swiss albino mice. To determine the incidence of micronuclei, mice were injected i.p. twice, at an interval of 24 hr with the drug at doses of 20, 100 and 200 mg/kg. Animals were killed 6 hr after the second dose and bone marrow was examined for the presence of micronuclei in developing erythrocytes. Ribavirin significantly (P less than 0.05) induced micronuclei in polychromatic erythrocytes at all doses. A study was conducted to investigate the cytogenetic effect of the drug on mitotic chromosomes. Ribavirin at 200 mg/kg/day was administered to mice for 3 and 5 days. Repeated treatment with the high dose of ribavirin produced a highly significant (P less than 0.02) increase in abnormal metaphase spreads. The results indicate that ribavirin is mutagenic to bone marrow cells of mice as evaluated by the micronucleus test and by chromosome analysis. [Rao KP, Rahiman MA; Mutat Res 224 (2): 213-8 (1989) ]**PEER REVIEWED** PubMed Abstract

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Rat oral 5.3 g/kg [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 809]**PEER REVIEWED**
  • LD50 Mouse oral 2 g/kg [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 809]**PEER REVIEWED**
  • LD50 Mouse ip 0.9-1.3 g/kg [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 809]**PEER REVIEWED**
  • LD50 Rat ip 2 g/kg [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 809]**PEER REVIEWED**

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Absorption, Distribution and Excretion

  • Ribavirin is absorbed systemically from the respiratory tract following nasal and oral inhalation. The bioavailability of ribavirin administered via nasal and oral inhalation has not been determined but may depend on the method of drug delivery during nebulization (eg, oxygen hood, face mask, oxygen tent). At a constant flow rate, the amount of drug delivered to the respiratory tract theoretically is directly related to the concentration of nebulized drug solution and the duration of inhalation therapy. In addition, alterations in the method of aerosol delivery can affect the amount of drug reaching the respiratory tract. The fraction of an inhaled dose of ribavirin that is deposited in the respiratory tract during oral and nasal inhalation of a nebulized solution containing 190 ug/L using a small particle aerosol generator has been estimated to average about 70%, but the actual amount deposited depends on several factors including respiratory rate and tidal volume. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 810]**PEER REVIEWED**
  • Peak plasma ribavirin concentrations generally appear to occur at the end of the inhalation period when the drug is inhaled orally and nasally using a small particle aerosol generator, and increase with increasing duration of the inhalation period. Following nasal and oral inhalation (via face mask) of 0.82 mg/kg/hr for 2.5 hr daily for 3 days in a limited number of pediatric patients, peak plasma ribavirin concentrations averaged 0.19 (range: 0.11-0.388) ug/mL. Peak plasma ribavirin concentrations averaged 0.275 (range: 0.21-0.35) or 1.1 (range: 0.45-2.18) ug/mL in a limited number of patients inhaling 0.82 mg/kg per hour for 5 or 8 hr daily, respectively, for 3 days, and averaged 1.7 (range: 0.38-3.58) ug/mL in a limited number of pediatric patients inhaling 0.82 mg/kg per hour via face mask, mist tent, or respirator for 20 hr daily for 5 days. Highest plasma concentrations for a given dosage of ribavirin appear to be achieved in patients receiving the drug from the aerosol generator via an endotracheal tube. ... Peak plasma ribavirin concentrations achieved with nasal and oral inhalation of usual dosages of the drug are less than concentrations that reportedly reduce respiratory syncytial virus plaque formation by 85-98%. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 810]**PEER REVIEWED**
  • Concentrations of ribavirin achieved in respiratory tract secretions in patients inhaling the drug nasally and orally are likely to be substantially greater than those achieved in plasma. In a limited number of pediatric patients who received a nasally and orally inhaled ribavirin dose of 0.82 mg/kg per hour for 8 hr daily for 3 days, peak concentrations of the drug in respiratory tract secretions (from endotracheal tube) ranged from 250-1925 ug/mL. In pediatric patients who received 0.82 mg/kg per hour via nasal and oral inhalation for 20 hr daily for 5 days, ribavirin concentrations in respiratory tract secretions (from endotracheal tube) ranged from 313-28,250 ug/mL during therapy, with peak concentrations averaging 3075 (range: 313-7050) ug/mL at the end of therapy. Concentrations of ribavirin achieved in respiratory tract secretions via nasal and oral inhalation are likely to be substantially greater than concentrations necessary to inhibit plaque formation of susceptible strains of respiratory syncytial virus in vitro; however, because respiratory syncytial virus is found within virus infected cells in the respiratory tract, the manufacturer states that intracellular respiratory tract drug concentrations may be more closely related to plasma ribavirin concentrations than to those measured in respiratory tract secretions. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 810]**PEER REVIEWED**
  • Ribavirin is rapidly absorbed following oral administration, with peak plasma concentrations of the drug occurring within 1-3 hr after multiple doses. However, the absolute bioavailability of ribavirin averages only 64% following oral administration because the drug undergoes first-pass metabolism. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 810]**PEER REVIEWED**
  • Following nasal and oral inhalation, highest ribavirin concentrations are found in the respiratory tract and erythrocytes. Following parenteral administration of single doses in monkeys and baboons, ribavirin and/or its metabolites are distributed in highest concentrations into skeletal muscle; blood cells, principally erythrocytes; and liver. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 811]**PEER REVIEWED**
  • Studies in animals and humans have shown that ribavirin and/or its metabolites accumulate in erythrocytes. The extent of accumulation of ribavirin and/or its metabolites in erythrocytes following inhalation of the drug has not been established, but, following oral administration of a single 3 mg/kg dose, erythrocyte concentrations of the drug have been reported to peak within approximately 4 days, exceeding concurrent plasma concentrations at 4 days by about 100 fold, and then declining with a half-life of about 40 days. During the initial 1-2 hr following oral administration of a single dose of the drug, erythrocyte concentrations increase at a rate similar to plasma concentrations; thereafter, erythrocyte concentrations continue to increase for about 4 days as plasma drug concentrations decline. Approximately 3% of a single ribavirin dose is present in erythrocytes 72 hr after oral administration. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 811]**PEER REVIEWED**
  • Ribavirin appears to distribute slowly into CSF. Following chronic (4-7 wks) oral administration of ribavirin in patients with acquired immunodeficiency syndrome or AlDS-related complex, CSF concentrations of the drug were approximately 70% of concurrent plasma concentrations. It is not known whether ribavirin crosses the placenta or distributes into milk in humans. The drug appears to be only minimally bound to plasma proteins. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 811]**PEER REVIEWED**
  • Elimination of /ribavirin/ from the respiratory tract may result from distribution across respiratory membranes, clearance by macrophages in the respiratory tract, and/or upward ciliary activity. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 8118]**PEER REVIEWED**
  • Ribavirin is excreted principally in urine. In healthy adults with normal renal function, approximately 53% of a single oral dose is excreted in urine within 72-80 hr, with about 33% excreted within the first 24 hr. Approximately 37, 30, and 30% of the fraction excreted in urine appears as unchanged drug, 1,2,4-triazole-3-carboxamide, and 1,2,4-triazole-3-carboxylic acid, respectively, within 1.5-2 hr, and approximately 17, 50, and 22%, respectively, within 24 hr. About 15% of a single oral dose is excreted in feces within 72 hr. Little, if any, ribavirin appears to be eliminated in expired CO2. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 811]**PEER REVIEWED**
  • There is extensive accumulation of ribavirin following multiple (twice daily) doses of the drug, such that peak plasma ribavirin concentrations at steady state are fourfold higher than those following a single dose. Following oral administration of single or multiple 600-mg doses of ribavirin (as capsules), mean peak plasma concentrations in adults average 0.782 or 3.7 ug/mL, respectively. In patients weighing more than 75 kg, ribavirin 1.2 g daily (as tablets) given with food for 12 weeks resulted in peak plasma ribavirin concentrations of 2.7 ug/mL. In children 5-16 years of age, mean peak plasma concentrations average 2.7-3.2 mcg/mL following ribavirin dosages of 12-15 mg/kg twice daily (as capsules). [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 811]**PEER REVIEWED**

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Metabolism/Metabolites

  • Ribavirin is metabolized principally to deribosylated ribavirin (the 1,2,4-triazole-3-carboxamide), probably in the liver; the antiviral activity of 1,2,4-triazole-3-carboxamide against various RNA and DNA viruses is reportedly similar to ribavirin. The drug is also metabolized to 1,2,4-triazole-3-carboxylic acid. In vitro, ribavirin has been shown to be metabolized to ribavirin-5'-monophosphate, -diphosphate, and -triphosphate, principally by intracellular phosphorylation of the drug via adenosine kinase and other cellular enzymes. It is likely that phosphorylation in vivo is necessary for the antiviral activity of the drug. Ribavirin also undergoes phosphorylation in erythrocytes, principally to ribavirin-5'-triphosphate; approximately 81, 16, and 3% of drug metabolized in erythrocytes is present as ribavirin-5'-triphosphate, -diphosphate, and -monophosphate, respectively. It has been suggested that prolonged distribution of the drug in erythrocytes may result from minimal phosphatase activity in these cells with transit of the drug out of cells dependent on dephosphorylation via phosphatases. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 811]**PEER REVIEWED**
  • Ribavirin has two pathways of metabolism: (i) a reversible phosphorylation pathway in nucleated cells; and (ii) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite. Ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are excreted renally. [Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 3083]**PEER REVIEWED**

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TSCA Test Submissions

  • None found

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Footnotes

1 Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.

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Web page last updated on May 14, 2008