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Absorption, metabolism, and excretion of [14C]viramidine, a prodrug of ribavirin, were studied in humans following a single oral dose (600 mg). Viramidine was rapidly absorbed, with a time to maximum concentration of the drug in plasma of 1.5 h. Viramidine and ribavirin accounted for only 4.3% and 42% of plasma area under the concentration-time curve (AUC) for radioactivity, respectively, indicating extensive conversion of viramidine to ribavirin, followed by further metabolism of ribavirin. The drug was largely trapped in red blood cells (RBC), with an RBC-to-plasma radioactivity AUC0-infinity ratio of 108. Excretion of total radioactivity in urine and feces accounted for 50.8% and 26.1% of the dose, respectively. The metabolic profile in urine (0 to 24 h) indicated that viramidine was excreted primarily as triazole carboxamide (TCONH2), triazole carboxylic acid nucleoside (TCOOH), and ribavirin with a small amount of unchanged viramidine, which each accounted for 64.1%, 17.0%, 15.7%, and 3.2% of urinary radioactivity, respectively. The amounts of unchanged viramidine (3.4% of dose) and ribavirin (10% of dose) in urine were small after oral administration of viramidine.

Ribavirin has recently been demonstrated to have efficacy in combination with alpha interferon for treatment of relapsed hepatitis C. The marked improvement in the response rate after treatment with the combination regimen (10-fold higher versus that from monotherapy with alpha interferon) highlights the importance of determining the absolute bioavailability of ribavirin as a first step in beginning to investigate the pharmacodynamics of the combination. The objective of this study was to determine the absolute bioavailability of ribavirin with an intravenous formulation containing ribavirin labeled with the stable isotope (13)C(3) ((13)C(3)-ribavirin) and unlabeled oral ribavirin. Six healthy volunteers received 150 mg of intravenous (13)C(3)-ribavirin followed 1 h later by a 400-mg oral dose of ribavirin. Samples of blood and urine were collected up to 169 h postdosing. Concentrations of (13)C(3)-ribavirin and unlabeled ribavirin were determined by a high-performance liquid chromatography tandem mass spectrometric method. All plasma and urine data were comodeled for labeled and unlabeled ribavirin by using both the two- and three-compartment models in the program ADAPT II. A three-compartment model was chosen for the pharmacokinetic analysis with the Akaike Information Criterion. The mean maximum concentrations of drug in plasma for intravenous and oral ribavirin were 4,187 and 638 ng/ml, respectively. The mean bioavailability was 51.8% +/- 21.8%, and the mean gamma-phase half-life was 37.0 +/- 14. 2 h. The mean renal clearance, metabolic clearance, and volume of distribution of the central compartment were 6.94 liters/h, 18.1 liters/h, and 17.8 liters, respectively. The use of the stable-isotope methodology has provided the best estimate of the absolute bioavailability of ribavirin that is currently available, as there was neither a period bias nor a washout effect to confound the data. The study demonstrated that the mean bioavailability for a 400-mg dose of ribavirin was 52%, which is higher than that previously reported in other investigations.

Ribavirin has been shown to have broad-spectrum antiviral. To study its tissue distribution and disappearance rate, a single dose of 10 mg/kg which contained 10 microCi of [14C]ribavirin was injected intravenously into rhesus monkeys and intramuscularly into monkeys and rats. Except for peak plasma concentrations and the initial phases of the plasma disappearance and urine excretion curves, no significant difference was observed between plasma, tissue, or urine values for intramuscularly or intravenously injected monkeys. Plasma disappearance curves were triphasic; plasma concentrations of ribavirin were similar for both monkeys and rats. Rats excreted ribavirin in the urine more rapidly and to a greater extent (82% excreted in 24 h) than did monkeys (60% excreted in 72 h). In the rat, only 3% of the injected [14C]ribavirin was detected in expired CO2. Therefore, for both species, urine was the major route for the elimination of labeled ribavirin and its metabolites from the body. In monkeys, the amount of parent drug in blood cells increased through 48 h and remained stable for 72 h, whereas in rats, ribavirin decreased at a rate similar to the plasma disappearance curve. Concentrations of ribavirin at 8 h were consistently higher in monkeys than in rats for all tissues except the brain. Thus, these differences in blood cellular components and organ content and in urine excretion suggested that there was greater tissue retention of ribavirin in monkeys than in rats.