The Bioavailability and Nonlinear Clearance of (–)-Carbovir in the Rat

Shu hui Huang, Rory P. Remmel, Cheryl L. Zimmerman

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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 µg/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 µg/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. Concomitant saturation of renal and nonrenal clearances might explain these findings. The oral bioavailability was about 20% at concentrations approximating 1 µg/ml in blood.

Original languageEnglish (US)
Pages (from-to)739-743
Number of pages5
JournalPharmaceutical Research: An Official Journal of the American Association of Pharmaceutical Scientists
Volume8
Issue number6
DOIs
StatePublished - Jun 1991

Keywords

  • (–)-carbovir
  • Sprague–Dawley rats
  • bioavailability
  • nonlinear clearance

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