Possible mechanism for pharmacokinetic interaction between lidocaine and mexiletine.
OBJECTIVE
Our objective was to elucidate the mechanism of pharmacokinetic interaction between lidocaine and mexiletine, because an unexpected increase in plasma lidocaine concentration accompanied by severe side effects was observed when mexiletine was administered to a patient with dilated cardiomyopathy.


METHODS
Plasma concentrations of lidocaine, its major metabolites, and mexiletine were measured in a patient with dilated cardiomyopathy. The lidocaine-mexiletine interaction was evaluated by examination of the effects of mexiletine on plasma concentration and the tissue distribution of lidocaine in rabbits in vivo, as well as on the in vitro lidocaine binding to phosphatidylserine, a binding constituent for weakly basic drugs.


RESULTS
Plasma lidocaine concentrations increased significantly when the oral dose of mexiletine was increased. This pharmacokinetic interaction was not attributable to a metabolic interaction as evaluated by plasma lidocaine metabolites concentrations. In rabbits, mexiletine seemed to decrease the total plasma clearance of lidocaine, resulting in increased plasma lidocaine concentrations. Mexiletine significantly reduced the tissue distribution of lidocaine to the kidneys and lungs. A strong displacing effect of mexiletine on the binding of lidocaine to phosphatidylserine was observed in vitro.


CONCLUSIONS
A drug interaction derived from the displacement of lidocaine from tissue binding sites by mexiletine that resulted in the increased plasma lidocaine concentrations was shown. This observation had implications for loading doses and acute effects of lidocaine in the concurrent therapy of lidocaine and mexiletine.
Maeda
Yorinobu
Y
Department of Pharmacy, Chugoku Rousai Hospital, 1-5-1 Hiro-Tagaya, Kure City, Hiroshima 737-0193, Japan.
Funakoshi
Sachiyo
S
Nakamura
Mamoru
M
Fukuzawa
Masataka
M
Kugaya
Yukimasa
Y
Yamasaki
Miho
M
Tsukiai
Satsuki
S
Murakami
Teruo
T
Takano
Mikihisa
M
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002311:Cardiomyopathy, Dilated / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D016018:Least-Squares Analysis; D008012:Lidocaine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008801:Mexiletine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011817:Rabbits; D017180:Tachycardia, Ventricular / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D008801:Mexiletine; D008012:Lidocaine