The pharmacokinetics of (-)-carbovir in rats. Evidence for nonlinear elimination

This study evaluated the pharmacokinetics and bioavailability of (-)-carbovir in rats following iv and po administration at doses of 10 to 120 mg/kg. The systemic clearance decreased 5-fold as the iv dose was increased from 10 to 120 mg/kg. At lower doses, (-)-carbovir was eliminated primarily by the renal route. The renal component of clearance became saturated as the dose was increased, leading to nonlinearity in the pharmacokinetics of (-)-carbovir. There were no changes in the metabolic clearance or the formation clearance of the major metabolite over the dose range of 10 to 60 mg/kg. The clearance value estimated following iv bolus administration was a "concentration averaged" value, and was not predictive of the steady-state concentrations. IV infusion studies indicated that at plasma concentrations less than 2500 ng/ml, the pharmacokinetics of (-)-carbovir were linear. The bioavailability was calculated for each treatment level and ranged from 43% at 10 mg/kg (iv and po) to 3% at 120 mg/kg (iv and po). The nonlinearity in the pharmacokinetics of (-)-carbovir must be taken into account when determining the bioavailability. At doses lower than 10 mg/kg, where the serum concentrations after iv administration would always remain in the linear range, the bioavailability may approach 50 to 60%. Poor bioavailability at high doses in the rat may not be reflective of the clinical situation, since the anticipated doses will be much lower than those administered in the rat.