Dose-dependent bioavailability of prazosin in beagle dogs

Prior to the introduction of an intravenous dosage form for use in humans, prazosin pharmacokinetic studies emphasizing clearance, hepatic extraction, and bioavailability were carried out in dogs. Two such canine studies reported significantly different values for the oral bioavailability of prazosin. This study investigated the differences in prazosin oral availability in beagle dogs. Three male animals were administered an intravenous (1 mg/kg) and three different oral doses (15, 5, and 1 mg) with a 7-day washout between study days. The mean predicted bioavailability, based on hepatic clearance and an estimate for liver blood flow, was 74%. The mean absolute bioavailabilities, determined for each dose in each animal by comparing dose-corrected areas under the plasma concentration-time curve, were 82, 27, and 23%. Although good agreement was evident in bioavailability between the 15-mg oral dose and what was predicted, calculated availabilities for the 5-mg and 1-mg oral doses were approximately one-third the predicted value. The results obtained from this study, together with data from the two previous studies, indicate that the bioavailability of prazosin in dogs is dose-dependent. Possible mechanisms for this observation are also presented.