PHARMACOKINETICS OF AMIODARONE IN SERUM AND TISSUE AND ITS RELEVANCE TO ANTI-ARRHYTHMIC ACTIVITY

Pharmacokinetics of amiodarone levels in serum. heart and adi-pose tissues following single or multiple dosing to rats. as well as its relation-ship to anti-arrhythmic activity, were studied. Serum drug levels were found tobe around 0.7μg/ml within 16 hours after a single oral dose of 50mg/kg. and ca.14μg/g of amiodarone was found in the heart tissue 2-8 hours after dosing,which tended to drop later. During the observation period. drug levels in adiposetissue rose continuously, being 35 times as high as that in the serum 16 hoursafter dosing. Groups of 4 rats were orally given doses of 50 mg/kg daily for up to 3-28days. Drug levels. in the serum and tissue were determined 4 hours following thelast dose. Steady state amiodarone concentrations in serum and heart tissue werefound to have approached on dayill, thus elimination half life was estimatedto be 38-44 hours. The heart/serum drug concentration ratio kept relatively con-stant (i. e., 14-16) within day 3-28, while the fat/serum drug concentrationratio rose continuously. being 106 on day 28. Evidently, owing to the deepperipheral compartment for amiodarone. the adipose tissue was poorly distributedin short durations, while the heart was considered to be the shallow "effect"compartment, thus the heart/serum ratio started to attain equilibrium on day 3.Besides, changes in serum reverse T_3 levels were found to parallel roughly tothose in serum and heart amiodarone levels during the multiple dosing period. Anti-arrhythmic experiments were carried out either in noradrenaline indu-ced rat arrhythmia model or in rats with their coronary arteries being ligated, Although marked anti-arrhythmic effect (principally a significant decrease ofventricular ectopia) was seen half an hour after a single iv. dose of 20 mg/kgin both models. the drug was no more effective 3 hours after the injection,meanwhile drug levels ranged 20. 7-39. 0μg/g in the heart, and 0.79-1.6μg/ml in the plasma. On the contrary, daily oral dose of 20 mg/kg for successivefive days was found to be effective as tested in both models, in spite of thefact that lower drug levels in the heart ranging 10. 0-12.2μg/g were found.The relevance of the above phenomena to the application of clinical therapeu-tic drug monitoring of amiodarone was discussed.