Mexiletine effects on theophylline disposition.
The effect of mexiletine administration on steady-state plasma theophylline concentrations was studied in eight normal healthy men in a prospective open label nonrandomized two-way crossover trial. Repeated doses of 300 mg of sustained-release theophylline were given every 12 hours for 9 days. Mexiletine hydrochloride, 200 mg every 8 hours, was given for five consecutive doses starting on the morning of day 6. Mexiletine increased theophylline levels in all subjects. Mean predose (trough) levels rose from 8.1 +/- 0.1 microgram.ml-1 to 13.4 +/- 0.6 micrograms.ml-1 and AUC(0-12) from 96.8 +/- 9.1 to 160.2 +/- 3.7 micrograms.ml-1.hr. Plasma clearance was reduced by mexiletine from 44.7 +/- 5.1 to 25.4 +/- 1.2 ml.hr-1. Both N-demethylated metabolites of theophylline were decreased by 60% by mexiletine, whose levels remained within its therapeutic range. Theophylline levels returned to pre-mexiletine values when this drug was discontinued. Mexiletine reduces theophylline clearance and increases its plasma concentration by inhibiting N-demethylation of theophylline. Plasma theophylline levels should be monitored when mexiletine is added.
Department of Internal Medicine, University of Kansas Medical Center, Kansas City 66103.
A
A
Hurwitz
J L
JL
Vacek
G W
GW
Botteron
M I
MI
Sztern
E M
EM
Hughes
A
A
Jayaraj
D000328:Adult; D003692:Delayed-Action Preparations; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008801:Mexiletine / Q000494:pharmacology*; D013806:Theophylline / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014527:Uric Acid / Q000031:analogs & derivatives / Q000097:blood
D003692:Delayed-Action Preparations; D008801:Mexiletine; D014527:Uric Acid; D013806:Theophylline; C031274:1,3-dimethyluric acid; C021183:1,7-dimethylxanthine