Nonlinear mixed effects model analysis of the pharmacokinetics of routinely administered bepridil in Japanese patients with arrhythmias.

This study was performed to evaluate variability in the pharmacokinetics of bepridil in 38 Japanese patients with arrhythmias, and to investigate the effects of aprindine as well as CYP2D6 and CYP3A5 polymorphisms on the oral clearance of bepridil. We determined the polymorphic alleles of CYP2D6 and CYP3A5 in each subject. The plasma concentration of bepridil at steady-state following repetitive oral administration was measured with an HPLC-based method, and the oral clearance was estimated using the nonlinear mixed effects model (NONMEM) program. Mean oral clearance was significantly greater in the patients with the CYP2D6*10 allele than in those without it. On the other hand, no significant effect of the CYP3A5 polymorphism was observed on the pharmacokinetics of bepridil. In addition, aprindine seemed to reduce the oral clearance of bepridil in the patients with the CYP2D6*10 allele.

Isolation of a major metabolite (i-OHAP) of aprindine and its identification as N-[3-(N,N-diethylamino)propyl]-N-phenyl-2-aminoindan-5-ol.

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.

Kinetics of frequency-dependent conduction delay by class I antiarrhythmic drugs in human atrium.

We investigated use-dependent prolongation of interatrial conduction time (IACT) by class I antiarrhythmic drugs in 16 patients. Changes in IACT at the initiation of atrial pacing were used to evaluate the onset kinetics. We examined recovery kinetics by giving a single extra stimulus with a varying coupling interval after discontinuing train stimulation. Time constants of the onset kinetics were 1.52 +/- 0.15/n(fast) and 0.087 +/- 0.031/n(slow) for mexiletine, 0.075 +/- 0.015/n for aprindine, 0.078 +/- 0.019/n for disopyramide, and 0.050 +/- 0.006/n for pilsicainide. The recovery time constants were 203 +/- 66 ms for mexiletine, 1,021 +/- 162 ms for aprindine, 993 +/- 101 ms for disopyramide, and 2,930 +/- 569 ms for pilsicainide. Class I antiarrhythmic drugs produced use-dependent IACT prolongation in humans, with characteristic kinetics for each agent similar to that of depression of the maximum upstroke velocity of cardiac action potential (Vmax) reported in in vitro studies.

The metabolism of aprindine in relation to the sparteine/debrisoquine polymorphism.

1. Incubation of the class I antiarrhythmic drug aprindine (AP) with human liver microsomes resulted in the formation of two hydroxylated metabolites (HA1 and HA2) and desethylaprindine which were identified by GC-mass spectrometry. In liver microsomes isolated from a poor metaboliser (PM) of sparteine no hydroxylated metabolites of AP were detected whereas AP N-dealkylation was unimpaired. Thus hydroxylation of AP is mediated by cytochrome P450 2D6 (CYP2D6). 2. AP was found to be a competitive inhibitor of CYP2D6 as indicated by its ability to impair the formation of (2S)-hydroxysparteine, 5,6-didehydrosparteine and 5-hydroxypropafenone by human liver microsomes. 3. These in vitro findings are consistent with a major role of CYP2D6 in the clearance of AP in vivo, with its ability to impair the metabolism of other CYP2D6 substrates in vivo, and an ability to cause phenocopying (conversion of extensive metaboliser phenotypes for sparteine/debrisoquine to apparent 'poor metabolisers).

Transport to intestinal lumen and peritoneal cavity of intravenously administered aprinidine in rats.

Transfer of aprindine from the blood into the intestinal lumen or into the peritoneal cavity was examined after intravenous administration of the drug at a dose of 5 mg/kg in rats. The amount of the drug transferred from the blood into the intestinal lumen was much greater than into the peritoneal cavity. The average amounts of aprindine transported into the intestinal lumen and the peritoneal cavity were 0.12 and 0.03% of the dose (5 mg/kg) in 120 min, respectively. Thus, a notable difference in the clearance values of the drug was obtained between the intestinal lumen (14.8 ml/h) and the peritoneal cavity (4.94 ml/h). The net water flux showed that secretion predominated in the peritoneal transport while absorption overbalanced secretion in the intestinal transport. It seems likely that a solvent drag effect by water movement did not contribute much to the transport of aprindine from the blood to the intestinal lumen or the peritoneal cavity. The differences in transport across the two membranes could be due to differences in the surface area and other geometrical factors. Differences could also be due to a difference in the pharmacologic effects of the drug which causes a decrease in tissue splanchnic perfusion.

Rapid and sensitive determination of aprindine in serum by gas chromatography using a surface ionization detector.

A rapid and highly sensitive method for the determination in serum of aprindine, an antiarrhythmic drug, was developed employing gas chromatography with a surface ionization detector. No interfering peak from endogenous substances appeared when an organic phase was directly injected into the system after single extraction from a serum sample. A standard curve obtained was linear up to the serum level of 6 micrograms/ml, and the limit of sensitivity was 16 pg. The method described is applicable to routine therapeutic monitoring of serum concentrations of aprindine.