ABSTRACT
Mexiletine is extensively metabolized in man, with less than 10% of the dose being excreted unchanged in urine. Clinical drug-drug interaction studies as well as in vitro drug metabolism studies suggest that CYP1A2, in addition to CYP2D6, is involved in the metabolism of mexiletine in man. Therefore, the objective of the study was to determine whether potential inhibition of CYP1A2 by the quinolone antibiotic agent ciprofloxacin would alter the stereoselective disposition of mexiletine. Nineteen healthy men (10 smokers and 9 nonsmokers) received a single 200-mg oral dose of racemic mexiletine hydrochloride on 2 occasions: once alone and once during concomitant administration of ciprofloxacin 750 mg BID (starting 3 days before and up to 2 days after the administration of mexiletine). Serial blood and urine samples were collected for 48 hours, and pharmacokinetic parameters were derived. Total clearances of R-(-)- and S-(+)-mexiletine were 42% and 63% higher in smokers compared with nonsmokers (P < 0.05). This observation is in agreement with increased clearance of mexiletine under conditions of increased CYP1A2 activity. On the other hand, ciprofloxacin administration only marginally decreased R-(-)- and S-(+)-mexiletine clearances (2 to 5 L/h; P < 0.05) secondary to a decrease in mexiletine nonrenal clearance. In conclusion, the increase in mexiletine nonrenal clearance in smokers and its decrease during the combined administration of ciprofloxacin confirm the role of CYP1A2 in the overall clearance of the drug. Nevertheless, results obtained in this study suggest that no major drug interaction is to be expected during the concomitant administration of ciprofloxacin and mexiletine in patients.
