ZATEBRADINE - PHARMACOKINETICS OF A NOVEL HEART-RATE-LOWERING AGENT AFTER INTRAVENOUS-INFUSION AND ORAL-ADMINISTRATION TO HEALTHY-SUBJECTS

Zatebradine (1; UL-FS 49 CL, 1,3,4,5-[tetrahydro-7,8-dimethoxy-3-[3-[12-(3,4-dimethoxyphenyl)ethyl]methylamino] propyl]-2H-3-benzazepin-2-on-hydrochloride) is the proposed INN name for a nonchiral, novel, specific heart-rate-lowering drug that is suitable for the treatment of stable angina pectoris. The pharmacokinetics of 1 and of total radioactivity in healthy volunteers (n = 6) were determined after intravenous infusion and oral administration of an experimental drug solution containing 7.5 mg (1.85 MBq) of C-14-labeled drug. Concentrations in plasma and urine were measured by a specific, sensitive, reversed-phase automated high-performance liquid chromatography system with fluorimetric detection at 285 nm Ex, 315 nm Em and by liquid scintillation counting. Recovery of total radioactivity was 89.8 +/- 2.3% (infusion) and 92.2 +/- 3.0% (oral). Renal elimination of total radioactivity was 62.5 +/- 2.0% (infusion) and 48.8 +/- 3.1% (oral). After intravenous infusion and oral administration, 27.3 +/- 2.4 and 43.4 +/- 3.9%, respectively, of the administered dose was eliminated in the feces. Absorption, based on renal excretion of total radioactivity following oral and intravenous dosing, was 79.2 +/- 15.3% (mean +/- standard deviation). Unchanged parent drug contributed 28.4 +/- 5.8% (infusion) and 12.4 +/- 3.7% (oral) of the dose to renal excretion. Zero to three minutes after cessation of the 20-min infusion, the maximum concentration of parent drug in plasma was 161.9 +/- 70.9 ng/mL. After oral administration, a mean peak concentration in plasma of 24.3 +/- 6.7 ng/mL (0.5 3 h postadministration) was reached. Data regarding levels of 1 in plasma could be adequately fitted with an open, two-compartment model. The dominant terminal half-life (infusion) of 1 was 2.80 +/- 0.8 h (range 1.82-3.40 h). Mean residence times were 3.2 +/- 0.8 h (infusion) and 4.6 +/- 0.8 h (oral administration), and total body clearances were 630 +/- 243 mL/min (infusion) and 1197 +/- 538 mL/min (oral). Absolute bioavailability was 51.5 +/- 17.8% (range 29.0-80.0%) based on data from the area under the curve of concentration in plasma versus time and 45.0 +/- 17.0% (range 30.0-70.0%) based on renal excretion of parent drug.