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.

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).

A model analysis for competitive binding of mexiletine and aprindine to the cardiac sodium channel.

A simulation model was developed to predict complex interaction between antiarrhythmic drugs and cardiac sodium channels. This model has four assumptions: (1) Vmax of the action potential is a linear indicator of available sodium channel conductance; (2) antiarrhythmic drugs block the channel by binding to a single common receptor site associated with the channel; (3) binding and dissociation rate constants differ for the three channel states: activated, inactivated and resting, and (4) both drug-free and drug-bound channels change states far more rapidly than binding and dissociation processes. Binding and dissociation rate constants for the three channel states were calculated from single cell experiments using guinea pig hearts. Vmax changes reflecting tonic and use-dependent sodium channel block in the presence of mexiletine and aprindine were simulated and compared with those obtained in the single cell experiments. The model predicted that 'tonic' Vmax inhibition would be enhanced, whereas 'use-dependent' ones would be attenuated after admixture of mexiletine with aprindine. The mechanisms would involve competitive interaction at the common receptor site. Single-cell experiments supported this prediction. We conclude that our simple two-drug binding model provides a useful tool to predict pharmacological interaction between class I antiarrhythmic drugs given in combination.

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.

Dose-dependent pharmacokinetics of aprindine in healthy volunteers.

The disposition of aprindine following a single oral dose can best be described by a two-compartment open model. The mean plasma half-life (t 1/2 beta) increased from 8.0 +/- 2.1 h (SD) after a 25 mg dose of 9.4 +/- 2.9 h after 50 mg and to 15.8 +/- 2.6 h after 100 mg, with a decrease in total plasma clearance (Cl/F) and volume of distribution at steady state (V dss/F) and during beta-phase (V d beta/F). The area under plasma concentration-time curve (AUC), maximum plasma concentration (C max) and the amount of unchanged aprindine excreted in the urine increased in a non-linear fashion with the increase in dose. The t 1/2 beta after multiple oral doses showed a 3-fold increase over the single dose value. These results indicate that aprindine shows dose-dependent non-linear kinetics.

Pharmacokinetic study of aprindine and moxaprindine in dogs.

Moxaprindine and aprindine were each administered to a group of six dogs at a single dose of 5.5 mg/kg by intravenous injection and at the same dose 14 days later by oral route. In each series the sequence of route of administration was randomized. In a second experiment, 8 to 12 weeks later, the dogs were treated for 5 successive days with the same drug at the dose of 5.5 mg/kg twice daily. Moxaprindine and aprindine are similar in several of their pharmacokinetic characteristics. Their plasma levels are suitably explained by a two-compartment open model. No significant differences are found between their respective terminal plasma half-lives nor their k12, k21 and kel values; on multiple dosing, the steady state is reached within 3 days with both drugs. However, the plasma levels of moxaprindine are twice as high as those of aprindine. Consequently the distribution volume of moxaprindine is half as small as that of aprindine. Moxaprindine is 95.3% protein bound at 1 microgram/ml and 93.6% at 2 microgram/ml; the corresponding values for aprindine are 98.3% and 98.1%. These differences may be of clinical significance as regards therapeutic effectiveness and safety of these two substances.

Alterations in regional myocardial distribution and arrhythmogenic effects of aprindine produced by coronary artery occlusion in the dog.

Little information exists regarding the effects of coronary artery occlusion on the distribution and actions of antiarrhythmic agents. We administered aprindine to dogs before, 5 min after, and 24 h after one-stage left anterior descending coronary artery (LAD) occlusion. Coronary artery occlusion performed after aprindine administration slowed the rate of disappearance of aprindine from the ischaemic zone compared with the normal zone, so that ischaemic zone aprindine concentrations averaged more than twice normal zone aprindine concentrations 1 h after LAD occlusion. When LAD occlusion was performed before aprindine administration, ischaemic zone aprindine concentrations were initially less than 15% of normal zone aprindine concentrations and increased with time to approach half of normal zone aprindine concentrations 70 min after LAD occlusion. Seventeen of 35 dogs (49%) receiving aprindine before LAD occlusion experienced sustained ventricular tachycardia or ventricular fibrillation, compared with 5/34 (14%) receiving aprindine immediately after LAD occlusion (P less than 0.01), 1/10 (10%) undergoing LAD occlusion without receiving aprindine (P less than 0.05) and 0/16 receiving aprindine without LAD occlusion (P less than 0.01). Aprindine administered 24 h after CO reduced premature ventricular complexes from a mean of 35 to 12 per 100 beats (P less than 0.01) occlusion importantly modifies the regional myocardial distribution of aprindine and its effects on ventricular arrhythmias after coronary artery occlusion.

The binding of aprindine to serum proteins with statistical considerations concerning the analysis of binding data.

The binding of the potent, basic antiarrhythmic agent aprindine to serum proteins was studied in solutions of human serum albumin (HSA, lyophilized, 98% pure, KABI) and in human sera. The percentual binding in serum (90.9-96.7%) was considerably higher than in HSA solutions. The binding in serum decreased from 95-97% to 91-93% as the aprindine concentration was raised from 4 to 15 micrograms/ml. The serum binding differed significantly in sera from three normal individuals. By plotting (Formula: see text), as a function of bound drug and performing statistical analysis of the curves a striking difference between the number of primary binding sites in serum and in HSA solution was found (N1 for the HSA solution was 0.0016 and for one serum it was 0.020 "per albumin molecule".) The association constants for the primary binding sites (K1) were 4.3 X 10(6)M-1 for serum and 2.1 X 10(6)M-1 for the HSA solution. Furthermore, the analysis indicated that considerably less than one secondary binding site was present for each albumin molecule in the HSA solution. Therefore, no binding of aprindine to albumin molecules has been demonstrated and it is concluded that the entire binding of aprindine in serum as well as in 98% HSA solutions may be due to the presence of acid protein molecules. In particular, low percentual binding in HSA solutions in spite of the high association constant can be explained by a very low concentration of the binding proteins. The addition of propranolol or phenprocoumon did not cause any displacement of aprindine. In the appendix statistical problems in the analysis of the binding curves are elucidated. The experimental variance and the statistical acceptability of the binding model are discussed.

Aprindine.

Aprindine is a long-acting antiarrhythmic agent, effective when administered orally or intravenously in the treatment of ventricular arrhythmias of varying etiologies. It may be especially useful in the treatment of the Wolff-Parkinson-White syndrome. To a lesser extent, it may be useful in the treatment of atrial arrhythmias. Side effects can be minimized by careful titration of the dose of aprindine. If the frequency of such serious side effects as cholestatic jaundice and agranulocytosis remains low enough, aprindine should prove to be a useful addition to currently available antiarrhythmic drugs.