INTERACTION BETWEEN AMIODARONE AND LIDOCAINE

We investigated the in vitro and in vivo interaction between amiodaron e and lidocaine, The interaction on a molecular level was first studie d in microsomes from 11 human livers. Close correlations between amiod arone N-monodesethylase activities and (a) the amounts of cytochrome P -4503A4 (CYP3A4), and (b) the rates of lidocaine N-monodesethylation w ere observed. Lidocaine inhibited amiodarone N-monodesethylation (K-i = 120 mu M) competitively; inversely, amiodarone suppressed lidocaine N-monodesethylase activity in the same manner (K-i = 47 mu M). Moreove r, the metabolite N-monodesethylamiodarone (DEA) was stable and inhibi ted lidocaine metabolism in a concentration-dependent manner. The in v ivo interaction was investigated in 6 cardiac patients. Each of them r eceived a dose of 1 mg/kg lidocaine hydrochloride intravenously (i.v.) nn three different occasions: before amiodarone treatment (control), and after cumulative doses of 3 g (phase I) and 13 g (phase II), respe ctively, amiodarone hydrochloride. The analysis of lidocaine pharmacok inetics showed an increase in lidocaine area under the curve (AUG) whe n amiodarone was administered, whereas that of N-monodesethylated lido caine decreased. Moreover, the systemic clearance of lidocaine decreas ed, while the elimination half-life (t1/2) and the distribution volume at steady state of lidocaine remained unchanged. The pharmacokinetic parameters during phase IT were the same as those during phase I, indi cating that the interaction had already occurred early in the loading phase of amiodarone administration. The interaction between amiodarone and lidocaine may be explained by the inhibition of CYP3A4 by amiodar one and/or by its main metabolite DEA.