Interaction between amiodarone and lidocaine.
We 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 microM) competitively; inversely, amiodarone suppressed lidocaine N-monodesethylase activity in the same manner (Ki = 47 microM). 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 occasions: before 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 (t1/2) and the distribution volume at steady state of lidocaine remained unchanged. The pharmacokinetic parameters during phase II were the same as those during phase 1, 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.
Cardiovascular Therapy Research Unit, University Hospital, Zurich, Switzerland.
H R
HR
Ha
R
R
Candinas
B
B
Stieger
U A
UA
Meyer
F
F
Follath
D000328:Adult; D000368:Aged; D000638:Amiodarone / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D001798:Blood Proteins / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008012:Lidocaine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011485:Protein Binding
D000889:Anti-Arrhythmia Agents; D001798:Blood Proteins; D003577:Cytochrome P-450 Enzyme System; D008012:Lidocaine; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000638:Amiodarone