The observation that 3 patients had unusually low plasma mexiletine levels while taking phenytoin prompted a pharmacokinetic study in 6 healthy subjects. After taking phenytoin 300mg daily for a week, mean AUC and half-life of a single 400mg dose of mexiletine were reduced by an average of about 50 % (half-life reduced from 17.2 to 8.4 hours) (See reference number 1).
The most likely explanation is that phenytoin increases metabolism of mexiletine by cytochrome P450 isoenzyme CYP1A2
Information seems to be limited to this report(See reference number 1) but interaction appears to be established. It seems likely that fall in mexiletine levels will be clinically important in some individuals. Monitor for mexiletine efficacy,and where possible levels. Raise dosage if necessary.
1. Begg EJ,Chinwah PM, Webb C, Day RO, Wade DN. Enhanced metabolism of mexiletine afterphenytoin administration. Br J Clin Pharmacol (1982) 14, 219–23.