Pharmacokinetics of Falipamil after Intravenous Administration to Humans

Abstract

Falipamil (2-[3-[3-(3, 4-dimethoxyphenetylmethylamino]propyl]-5, 6-dimethoxyphthalamidine; 1) is a new specific bradycardic agent for the treatment of sinus tachycardia. Pharmacokinetics of falipamil in humans) (n = 6) was determined in plasma and urine after iv administration of 100mg (1.85 MBq) per person of 14C-labeled drug by liquid scintillation counting and by a specific, sensitive reversed-phase totally automated HPLC system with fluorimetric detection. Recovery of total radioactivity was 91.8 ± 3.7%, with 68.2 ± 4.3% in urine and 23.6 ± 2.5% in the feces. The majority of radioactivity was excreted within 24 to 48h. The parent drug, falipamil (1), and its N-desmethyl-metabolite (2), which is ∼100 times less active than 1, contributed 14.1 ± 1.6 and 4.5 ± 0.7%, respectively, of the dose to urinary excretion. Plasma protein binding of 1 and 2 was 87.9 ± 1.2 (concentration range: 2000–8000 ng/mL) and 89.7 ± 0.5% (concentration range: 62.5–1000 ng/mL), respectively. Plasma concentrations of 1 peaked at 2min at 724 ± 173 ng/mL, declined biphasically, and were fitted to a two-compartment open model. Plasma concentrations of 2 were very low, in all cases ranging from 0 to 35 ng/mL. The dominant terminal half-life (β-phase) of 1 from plasma was 1.8 ± 0.6h (range 1.4–2.9 h), mean residence time was 2.4 ± 0.4 h, total body clearance was 1108.5 ± 119mL/min, and renal clearance was 117 ± 20mL/min. All parameters demonstrated very low intersubject variability.