Pharmacokinetics and metabolism of [14C]viramidine in rats and cynomolgus monkeys

Abstract

The pharmacokinetics of [(14)C]viramidine, a prodrug of ribavirin, were studied in rats (30 mg/kg of body weight) and monkeys (10 mg/kg) following intravenous (i.v.) and oral administration. The levels of oral absorption and bioavailabilities were 61.7 and 9.91%, respectively, in rats and 43.9 and 13.6%, respectively, in monkeys. Following i.v. administration, the elimination half-lives were 2.7 h in rats and 28.9 h in monkeys. Total body clearances were 14.0 liters/h/kg in rats and 1.23 liters/h/kg in monkeys; the apparent volumes of distribution were 15.6 liters/kg in rats and 18.6 liters/kg in monkeys. Following oral administration, viramidine was extensively converted to ribavirin, followed by further metabolism of ribavirin in both species, with a faster rate of metabolism in rats than in monkeys. In rats, excretion of total radioactivity in urine accounted for 77.0% of the i.v. dose and 60.8% of the oral dose, while in monkeys it accounted for 44.4% of the i.v. dose and 39.0% of the oral dose. The amount of unchanged viramidine and ribavirin in urine was small in both species after i.v. and oral administration of viramidine.

FIG. 1.

Chemical structures of viramidine and ribavirin.

FIG. 2.

Concentrations of viramidine and ribavirin in rat and monkey plasma following i.v. (IV) and oral dosing of viramidine

FIG. 3.

Metabolic profile of [¹⁴C]viramidine in rat and monkey plasma and urine following i.v. (IV) and oral (PO) dosing of viramidine.