ABSTRACT
i-OHAP, a major metabolite of aprindine (AP), was isolated by TLC from rat feces and identified as N-13-(N,N-diethylamino)propyl]-N-phenyl-2-aminoindan-5-ol, based on 1H-NMR, the H-H correlation spectroscopy (COSY) spectrum, MS and LC-MS. Its structure was also confirmed by comparison with the synthesized compound. The hydroxy group of i-OHAP was located at the 5-position of the indan ring. AP is a prochiral compound, and the metabolism of AP to i-OHAP was stereoselective. The ratio of (+)/(-)-i-OHAP in rat feces and in human urine was about 5 and 15, respectively.
Subject(s)
Anti-Arrhythmia Agents/pharmacokinetics , Aprindine/analogs & derivatives , Aprindine/pharmacokinetics , Adult , Animals , Aprindine/metabolism , Aprindine/urine , Biotransformation , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Feces/chemistry , Female , Humans , Magnetic Resonance Spectroscopy , Male , Rats , Rats, Wistar , StereoisomerismABSTRACT
In 36 patients with cardiac arrhythmias (predominantly ventricular premature beats), who were on oral aprindine long-term therapy with 50 to 400 mg daily, plasma levels were measured by gas chromatography after 3.5 hours of the last administration. There was a general dependency of plasma levels on the given dose, however, with considerable overlapping in individual values. In 24 patients the arrhythmias ceased, in six patients there was a clear, in two a moderate improvement. There was no clear therapeutic effect in four patients who were treated with a daily dose of 50 and 100 mg, respectively. Among the 36 patients, three who had plasma levels exceeding 2 micrograms/ml developed tremor and dizziness. After dose-reduction these side effects disappeared. The present results suggest that therapeutic plasma levels of aprindine are in the range of 1.0 to 1.75 micrograms/ml. A plasma level of 2 micrograms/ml should not be exceeded because of the possibility of side-effects. In six healthy males time-concentration curves of aprindine and its metabolites in plasma and urine were measured by gas chromatography. From the results a two-compartment model may be applied, the half-life of elimination was calculated to be 37 hours (plasma) and 31 hours (urine). With respect to the metabolites, in plasma only des-ethyl-aprindine (DEAP), in urine DEAP, hydroxy-, des-phenyl- and des-indanyl-aprindine could be found. Unlike aprindine, the DEAP-concentration curve in plasma showed a very slight decrease until the end of the 96-hour period of determination.
