Interaction Between Amiodarone and Lidocaine

• Published in: Journal of cardiovascular pharmacology Vol. 28; no. 4; pp. 533 - 539
• Main Authors: Ha, Huy Riem, Candinas, Reto, Stieger, Bruno, Meyer, Urs A, Follath, Ferenc
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Lippincott-Raven Publishers 01-10-1996; Hagerstown, MD Lippincott
• Subjects: Adult; Aged; Amiodarone - administration & dosage; Amiodarone - pharmacokinetics; Amiodarone - pharmacology; Anti-Arrhythmia Agents - pharmacokinetics; Anti-Arrhythmia Agents - pharmacology; Antiarythmic agents; Arrhythmias, Cardiac - drug therapy; Biological and medical sciences; Blood Proteins - metabolism; Cardiovascular system; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - metabolism; Drug Interactions; Drug Therapy, Combination; Female; Humans; In Vitro Techniques; Kinetics; Lidocaine - administration & dosage; Lidocaine - pharmacokinetics; Lidocaine - pharmacology; Male; Medical sciences; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Middle Aged; Mixed Function Oxygenases - metabolism; Pharmacology. Drug treatments; Protein Binding; Human; Digestive system; Cytochrome P450; Liver; Microsome; Metabolism; In vitro; Iodine Organic compounds; Local anesthetic; In vivo; Drug interaction; Pharmacokinetics; Antiarrhythmia agent
• ISSN: 0160-2446; 1533-4023
• DOI: 10.1097/00005344-199610000-00009

SUMMARYWe investigated the in vitro and in vivo interaction between amiodarone and lidocaine. The interaction on a molecular level was first studied in microsomes from 11 human livers. Close correlations between amiodarone N-monodesethylase activities and (a) the amounts of cytochrome P-4503A4 (CYP3A4), and (b) the rates of lidocaine N-monodesethylation were observed. Lidocaine inhibited amiodarone N-monodesethylation (Ki = 120 μM) competitively; inversely, amiodarone suppressed lidocaine N-monodesethylase activity in the same manner (Ki = 47 μM). Moreover, the metabolite N-monodesethylamiodarone (DEA) was stable and inhibited lidocaine metabolism in a concentration-dependent manner. The in vivo interaction was investigated in 6 cardiac patients. Each of them received a dose of 1 mg/kg lidocaine hydrochloride intravenously (i.v.) on three different occasionsbefore amiodarone treatment (control), and after cumulative doses of 3 g (phase I) and 13 g (phase II), respectively, amiodarone hydrochloride. The analysis of lidocaine pharmacokinetics showed an increase in lidocaine area under the curve (AUC) when amiodarone was administered, whereas that of N-monodesethylated lidocaine decreased. Moreover, the systemic clearance of lidocaine decreased, while the elimination half-life (t½) and the distribution volume at steady state of lidocaine remained unchanged. The pharmacokinetic parameters during phase II were the same as those during phase I, indicating 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 amiodarone and/or by its main metabolite DEA.