Pharmacokinetics of carvedilol after intravenous and oral administration in conscious healthy dogs.

OBJECTIVE

To determine the pharmacokinetics of carvedilol administered IV and orally and determine the dose of carvedilol required to maintain plasma concentrations associated with anticipated therapeutic efficacy when administered orally to dogs.

ANIMALS: 8 healthy dogs.

PROCEDURES: Blood samples were collected for 24 hours after single doses of carvedilol were administered IV (175 microg/kg) or PO (1.5 mg/kg) by use of a crossover nonrandomized design. Carvedilol concentrations were detected in plasma by use of high-performance liquid chromatography. Plasma drug concentration versus time curves were subjected to noncompartmental pharmacokinetic analysis.

RESULTS

The median peak concentration (extrapolated) of carvedilol after IV administration was 476 ng/mL (range, 203 to 1,920 ng/mL), elimination half-life (t(1/2)) was 282 minutes (range, 19 to 1,021 minutes), and mean residence time (MRT) was 360 minutes (range, 19 to 819 minutes). Volume of distribution at steady state was 2.0 L/kg (range, 0.7 to 4.3 L/kg). After oral administration of carvedilol, the median peak concentration was 24 microg/mL (range, 9 to 173 microg/mL), time to maximum concentration was 90 minutes (range, 60 to 180 minutes), t(1/2) was 82 minutes (range, 64 to 138 minutes), and MRT was 182 minutes (range, 112 to 254 minutes). Median bioavailability after oral administration of carvedilol was 2.1% (range, 0.4% to 54%).

CONCLUSIONS AND CLINICAL RELEVANCE: Although results suggested a 3-hour dosing interval on the basis of MRT, pharmacodynamic studies investigating the duration of beta-adrenoreceptor blockade provide a more accurate basis for determining the dosing interval of carvedilol.