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.
Brouwer
K R
KR
Department of Drug Metabolism, Glaxo, Inc., Research Triangle Park, NC 27709.
St Claire
R L
RL
Lagarde
J
J
Patanella
J E
JE
Walsh
J S
JS
Miwa
G T
GT
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D015224:Dideoxynucleosides / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D007262:Infusions, Intravenous; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000998:Antiviral Agents; D015224:Dideoxynucleosides; C057503:carbovir