Pharmacokinetics of ribavirin aerosol in mice

Abstract

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 ...

Aerosol and intraperitoneal administration of ribavirin and ribavirin triacetate: pharmacokinetics and protection of mice against intracerebral infection with influenza A/WSN virus

“…We have previously shown that ribavirin administered by small-particle aerosol (SPA) reaches the brain and achieves concentrations which should be sufficient for antiviral effectiveness (4,8). However, parenteral administration of ribavirin was not compared.…”

“…In this report, we describe the pharmacokinetics and effects of ribavirin and ribavirin-2',3',5'-triacetate SPA treatment. Mice were placed in sealed plastic cages and exposed to aerosols as described previously (4,21). The aerosol generator and particle characteristics were the same as previously described (7,20).…”

“…The treatment period for infected mice was for 2 h, twice daily (7 am and 3 pm) for 10 days (days + 1 through + 10). The estimated dose of drug retained by the mice was calculated from the amount of drug in the aerosol, the minute volume, and duration of treatment as previously described (4,21). In the pharmacokinetic experiments, three randomly chosen animals were used for each datum point.…”

“…Blood was mixed with 0. 13,000 x g for 5 min to remove debris, deproteinized by ultrafiltration through CF25 cones, and chromatographed on a phenylboronate affinity column as previously described (4,17,20 Pharmacokinetics following ribavirin and RTA aerosol administration. Protection experiments suggested that RTA administered by aerosol was an effective mode of treatment for influenza virus encephalitis.…”

“…Although ribavirin has been shown to cross the blood-brain barrier in both mice (4) and humans (1,12), it has not been very effective in preventing neurological symptoms or diseases caused by viruses. In a herpes simplex virus type 1-mouse encephalitis model, ribavirin administered either subcutaneously or intraperitoneally (i.p.)…”