Prazosin first-pass metabolism and hepatic extraction in the dog

The short half-life, low plasma concentrations, and extensive biotransformation of prazosin suggest that it might be subject to extensive first-pass metabolism. Bioavailability, disposition, and hepatic extraction were studied in the dog. In conscious dogs whole blood prazosin concentrations were measured after oral and intravenous administration of the drug. Anesthetized dogs were used to measure prazosin concentrations in arterial and hepatic venous blood samples drawn simultaneously. The bioavailability of prazosin was 0.38 +/- 0.11. In anesthetized dogs the hepatic extraction of prazosin was 0.47 +/- 0.08 for a predicted availability of 0.53 +/- 0.08. Pharmacokinetic parameters were similar in conscious and anesthetized animals. Following intravenous administration to conscious dogs, prazosin concentrations in whole blood declined with a fast half-life of 3.9 +/- 1.74 min and a slow half-life of 153 +/- 24 min, the volume of distribution at steady state being 48.6 +/- 15.3 liters in dogs (mean weight, 22.6 kg). We conclude that prazosin availability following oral administration is low and that first-pass hepatic metabolism is largely responsible for this. A one-compartment model adequately describes prazosin pharmacokinetics in the dog.