The effect of cigarette smoking on the kinetics of a single, 200 mg, oral dose of the antiarrhythmic drug mexiletine was investigated in healthy subjects. Cigarette smoking had no effect on absorption or distribution of the drug, but it significantly reduced the elimination t1/2 from 11.1 +/- 3.4 to 7.2 +/- 1.8 hours; the effect on clearance was less significant. Determination of the urinary concentrations of the three major metabolites of mexiletine (mexiletine glucuronide conjugate, hydroxymethylmexiletine, and p-hydroxymexiletine) indicated that cigarette smoking selectively induced conjugation of mexiletine with glucuronic acid as well as aliphatic hydroxylation to yield hydroxymethylmexiletine, but that it had no effect on the formation of p-hydroxymexiletine.