PHARMACOKINETICS AND PLASMA-PROTEIN BINDING OF BRB-I-28, A NOVEL ANTIARRHYTHMIC AGENT, IN DOGS

The pharmacokinetics and plasma protein binding of BRB-I-28, a novel antiarrhythmic agent, were investigated in dogs. The plasma concentration-time profile of BRB-I-28, following an intravenous bolus dose of 10 mg/kg, can be adequately described by a 2-compartment open model. The mean volume of distribution at steady-state (Vd(ss)) was 8.759 L/kg, the mean total systemic clearance (CL) was 1.289 ml/h/kg, and the mean elimination half-life (t1/2beta) was 4.645 hours. Following intravenous administration, approximately 1.85% of the dose was excreted in the urine (0 to 48 hours) as parent drug. Changes in plasma concentrations, after oral administration of BRB-I-28 20 mg/kg, were best described by a 1-compartment open model. BRB-I-28 was rapidly absorbed (t(max) = 1.22 hours and C(max) = 1.59 mg/L) with a rapid elimination rate (t1/2kel = 1.583 hours). Oral bioavailability was estimated to be 44.5%. Only 2.56% of the 20 mg/kg oral dose was excreted via the urine (0 to 48 hours). In vitro binding of BRB-I-28 to plasma protein was 29.7 +/- 10.3% at concentrations of 4 to 16 mg/L. In vivo binding of BRB-I-28 to plasma protein was 24.0 +/- 8.7%. Extensive distribution of BRB-I-28 may be due to its low binding to plasma protein. Low oral bioavailability and limited elimination of free parent BRB-I-28 in urine indicates that BRB-I-28 may undergo extensive metabolism, which may be the reason for its short duration of pharmacological effects.