The bioavailability and nonlinear clearance of (-)-carbovir in the rat.
The pharmacokinetics and bioavailability of (+/-)-carbovir, a carbocyclic nucleoside active against human immunodeficiency virus, have been described previously. To determine the bioavailability of (-)-carbovir, the biologically active enantiomer, four male Sprague-Dawley rats received 18 mg/kg of (-)-carbovir through the jugular vein and 54 mg/kg orally. Following the pilot studies, five rats were randomly assigned to receive (-)-carbovir in a three-way crossover design as either a single 18-mg/kg iv bolus, a single 54-mg/kg oral dose, or a single iv infusion of 18 mg/kg to achieve a target steady-state concentration (Css) of 1 micrograms/ml, the peak concentration after an oral dose. Blood and urine samples were analyzed by an improved ion-paired reversed-phase HPLC method with fluorescence detection. Blood concentrations of (-)-carbovir declined in a biphasic manner after the iv bolus dose. The terminal half-life was 116 and 106 min after the iv bolus and oral dose, respectively. The blood/plasma distribution ratio was approximately 1.0 in the range of 1 to 10 micrograms/ml of (-)-carbovir in blood. The free fraction in serum was concentration dependent. Significant differences in the renal, nonrenal, and total-body clearances after the iv bolus and iv infusion suggested nonlinear elimination of (-)-carbovir. The oral bioavailabilities derived from blood data were significantly different when the iv bolus was used as a reference rather than the iv infusion. However, the bioavailabilities were not significantly different when the total urinary excretion of unchanged (-)-carbovir after iv bolus or infusion was used as a reference.(ABSTRACT TRUNCATED AT 250 WORDS)
Huang
S H
SH
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis 55455.
Remmel
R P
RP
Zimmerman
C L
CL
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D015224:Dideoxynucleosides / Q000493:pharmacokinetics*; D008297:Male; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains
D000998:Antiviral Agents; D015224:Dideoxynucleosides; C057503:carbovir