Metabolic disposition of ajmaline.

Urine was collected from six patients receiving a continuous infusion of 20 mg/h ajmaline. Pooled urine was extracted with and without enzymatic conjugate cleavage or hydrolysis with concentrated hydrochloric acid. The extracts were analyzed by gas chromatography/mass spectrometry. Ajmaline and its metabolites in urine were identified in the form of their acetylated derivatives. Twenty two different acetylated derivatives of ajmaline and its metabolites could be detected. Three of these derivatives were artifacts generated by acetylation and/or thermal decomposition. The major metabolic pathways were mono- and di-hydroxylation of the benzene ring with subsequent O-methylation, reduction of the C-21, oxidation of the C-17 and C-21-hydroxyl function, N-oxidation, and a combination of these metabolic steps. Ajmaline and its metabolites were mainly excreted in the form of their conjugates. Furthermore, the interference of sparteine, debrisoquine, quinidine, and nifedipine with ajmaline metabolism was studied with semiquantitative thin-layer chromatography. Ajmaline metabolism was inhibited by co-administration of sparteine or quinidine, but not by debrisoquine or nifedipine. Sparteine most likely competed with ajmaline metabolism. Quinidine probably bound competitively to ajmaline-metabolizing enzymes without being metabolized itself. Additionally, the metabolic ratio of hydroxyajmaline/ajmaline in urine was determined in 9 extensive metabolizers and one poor metabolizer of dextromethorphan. The poor metabolizer had a significantly reduced metabolic ratio of hydroxyajmaline/ajmaline, which indicates that ajmaline metabolism probably co-segregates with polymorphic sparteine/debrisoquine/dextromethorphan metabolism.

The pharmacokinetics and organ distribution of ajmaline and quindine in the mouse.

After i.v. infusion into mice (lasting 10 s) the time courses of ajmaline and quinidine concentrations in blood, heart, lung, liver, and brain were studied. The drugs were assayed by a spectrofluorophotometric procedure. Blood concentration data obtained were fitted graphically and calculations were performed in accordance with an open two compartment model. Blood kinetic data were very similar for both alkaloids. A rapid distribution phase with a t0.5alpha of 3.0 min for ajmaline and 2.5 min for quindine was followed by a disposition phase with a t0.5beta of 16 min for ajmaline and 20 min for quinidine. High tissue accumulation of both alkaloids was found in lung, liver, and heart and this is also reflected by the volume of distribution Vdbeta, which was 136 ml for ajmaline and 116 ml for quinidine (body weight of the mice = 31 g). With equilibrium dialysis a 62% binding of ajmaline and a 77% binding of quinidine to mouse blood constituents was found. Both drugs were highly metabolized since only 5% of a given dose was excreted unchanged in the urine.