Pharmacokinetics of Lorcainide in Man

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Abstract
A gas liquid chromatographic assay was developed to measure in plasma and urine concentrations of the new antiarrhythmic drug lorcainide, its dealkylated metabolite and an added internal standard of similar structure. The limit of sensitivity was 10ng/ml plasma. In 5 healthy volunteers and in 6 patients with ventricular premature beats (VPB) the pharmacokinetics were determined after a single intravenous dose of 100mg. In 4 of the patients with VPB, the disposition was also evaluated under steady-state conditions following oral administration of 100mg twice daily. In 4 of the healthy volunteers, the bioavailability of a single 100mg (n = 2) and 150mg (n = 2) oral dose was determined. In an additional crossover experiment, bioavailability of a single oral dose of 100 and 200mg was also measured in 2 patients with VPB. Less than 2% of the intravenous dose could be recovered as unchanged lorcainide in the urine, indicating extensive metabolism. The drug was bound to plasma proteins to the extent of 85.0 ± 5.0% (mean ± SD) in healthy subjects and 83.3 ± 2.9% in patients with VPB. Since the plasma levels declined biexponentially after an intravenous dose, data were analysed according to a 2-compartment open model. The elimination half-life (t1/2β) of 5.1 ± 0.6h (healthy subjects) was somewhat longer (p = 0.02) in patients with VPB (7.6 ± 2.2h), but total plasma or blood clearance were very similar; the latter approaching a normal liver blood flow of 1.5L/min. The apparent distribution volumes Vdβ (8.6 ± 2.4L/kg vs 10.7 ± 4.2L/kg) and Vdss(6.4 ± 2.4L/kg vs 8.8 ± 3.4L/kg) showed no statistically significant difference between the healthy subjects and patients. After oral doses, high and saturable first-pass hepatic metabolism seems to exist. The crossover experiments in 4 subjects indicated bioavailability of about 1 to 4.5 % after a single 100mg dose, between 7 and 20 % after a 150mg dose, and between 35 and 65 % after a 200mg dose. In contrast, 3 of 4 patients with VPB on oral maintenance therapy exhibited bioavailability of 100%. This indicates that lorcainide belongs to the group of drugs exhibiting non-linear elimination kinetics.