Zatebradine (1; UL-FS 49 CL; 1, 3, 4, 5-[tetrahydro-7, 8-dimethoxy-3-[3-[[2-(3, 4-dimethoxyphenyl)ethyl]methylamino]propyl]-2 H -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 14 C-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.
