The pharmacokinetics and organ distribution of ajmaline and quinidine in the mouse

Aiba

Journal of Pharmacy and Pharmacology

et al. 2001

The effect of renal dysfunction on the bioavailability of ajmaline has been investigated in rats, where experimental renal dysfunction was induced by subcutaneous injection of uranyl nitrate (10 mg kg(-1)). Renal dysfunction did not cause any change in the blood ajmaline concentration after intravenous administration (2 mg kg(-1)), but it increased the blood ajmaline concentration by approximately 2.8-fold after intraduodenal administration (10 mg kg(-1)). The availability of ajmaline in control rats was 16.7%, whereas the availability was increased to 41.1% in rats with renal dysfunction. The unbound fraction in the blood and the metabolic activity in the liver, was assessed with the 10000-g supernatant fraction and with isolated hepatocytes, respectively. The values were found to be similar in both groups. The blood concentration following intraportal infusion was only slightly increased in rats with renal dysfunction, but the hepatic first-pass extraction was infusion rate-dependent and saturable. The initial absorption rate of ajmaline from the small intestine in rats with renal dysfunction was significantly greater compared with control rats. These results indicated that the increased availability of ajmaline in renal dysfunction was mainly a result of partially saturated extraction in the liver, which was caused by an increased absorption rate in the intestine and non-linear extraction in the liver.

Section: Discussionmentioning

confidence: 88%

Effect of experimental renal dysfunction on bioavailability of ajmaline in rats

Aiba

Journal of Pharmacy and Pharmacology

et al. 2001

“…This was probably related to the mechanism of ajmaline clearance. Ajmaline is poorly excreted in the urine (Kleinsorge & Gaida, 1961;Iven, 1977) and avidly extracted by the liver (Yamada et al, 1986). Moreover, we have shown that the total clearance of ajmaline is decreased in rats with acute myocardial ischaemia compared with sham-operated control rats (Hashimoto et al, 1986).…”

Section: Discussionmentioning

confidence: 66%

Pharmacokinetics and dromotropic activity of ajmaline in rats with hyperthyroidism

Kamiya

et al. 1989

British J Pharmacology

1 The pharmacokinetics and the dromotropic action (increased PQ interval) of intravenously administered adjmaline (2mgkg-1) were studied in hyperthyroid rats with sinus tachycardia. The hyperthyroidism was induced by intraperitonal injection of 3,5,3'-triiodo-L-thyronine (0.5mg kg1) for 4 days. 2 The change in the ajmaline concentration in whole blood could be described by a biexponential equation. The steady state distribution volume of ajmaline decreased from 4.811 kg' in control rats to 3.801kg-' in hyperthyroid rats and the total body blood clearance was slightly higher in hyperthyroid rats than in control rats. 3 Ajmaline exhibited a saturable binding to rat plasma proteins, and one kind of binding site was found in the observed range of concentrations. The binding capacity was 2 fold higher in hyperthyroid rats than in control rats. 4 On the basis of the plasma unbound concentration, ajmaline exhibited an increased negative dromotropic activity in hyperthyroid rats compared with control rats. 5 A positive correlation was found between the pacing rate and the dromotropic action of ajmaline on atrioventricular conduction in isolated perfused hearts. There was no significant difference in the rate-dependence of the effect of ajmaline on the heart between control and hyperthyroid rats. 6 Our findings suggest that the increased dromotropic activity of ajmaline is mainly due to the increased heart rate in hyperthyroid rats.

“…The heart is generally considered to be in rapid distribution equilibrium with the central pharmacokinetic compartment because it is highly perfused. In fact, the ajmaline concentration in the heart was reported to be rapidly equilibrated with blood in the normal mouse (Iven, 1977). However, if the rate of drug equilibration between blood and myocardium is related to perfusion, then ischaemic areas of myocardium should behave as a kinetically different compartment.…”

Section: Discussionmentioning

confidence: 99%

Regional myocardial ajmaline concentration and antiarrhythmic activity for ischaemia‐ and reperfusion‐induced arrhythmias in rats

Okumura

et al. 1988

British J Pharmacology

1 Antiarrhythmic actions of ajmaline against ischaemia (left coronary artery occlusion for 15 min) and subsequent reperfusion-induced arrhythmias were investigated in anaesthetized rats. 2 Ajmaline (2mg kg-, i.v.) was effective in suppressing ischaemia-induced arrhythmias whether given pre-or post-occlusion. 3 Ajmaline diminished the reperfusion-induced arrhythmias completely when given pre-occlusion but had little effect when given post-occlusion. 4 Reperfusion-induced increases in plasma enzyme activities of lactate dehydrogenase, glutamateoxaloacetate transaminase and creatine phosphokinase were prevented more effectively when ajmaline was given pre-occlusion rather than post-occlusion. 5 Fifteen min post-occlusion, the ajmaline concentrations in the ischaemic ventricle were 18.42 + 1.66 and 1.18 + 0.15 ygg-for pre-and post-occlusion administration, respectively. However, ajmaline concentrations in whole blood and normal ventricle were not significantly different between pre-and post-occlusion administration. 6 We suggest that the beneficial effect of ajmaline against reperfusion-induced arrhythmias is related to the ischaemic myocardial concentration of ajmaline which is markedly affected by the time of drug administration (i.e. pre-and post-occlusion).