Stereoselective disposition of the antiarrhythmic agent mexiletine during the concomitant administration of caffeine

Caffeine consumption is extensive in industrialized countries and its role in drug-drug interactions is often overlooked. CYP1A2, the major cytochrome P450 isoform involved in the metabolism of caffeine, has also been implica ted in the formation of N-hydroxymexiletine the major metabolite of mexilet ine. Therefore, the objective of this study was to assess the effects of a clinically relevant dosage of caffeine on the stereoselective disposition o f mexiletine. Fourteen healthy volunteers-10 extensive metabolizers (EMs) a nd 4 poor metabolizers (PMs) of CYP2D6-received a single 200 mg oral dose o f racemic mexiletine hydrochloride on two occasions (1 week apart): once by itself and once during administration of caffeine (100 mg four times daily ). Serial blood and urine samples were collected and pharmacokinetic parame ters were estimated. Although the total clearance of mexiletine was not sig nificantly altered by the coadministration of caffeine in EMs and PMs, a st ereoselective decrease (16% in EMs and 14% in PMs) in the urinary recovery of N-hydroxymexiletine from the R-(-)-enantiomer was observed. Also, the pa rtial metabolic clearance of R-(-)-mexiletine to N-hydroxymexiletine glucur onide was reduced from 126 +/- 48 mL/min to 106 +/- 32 mL/min and 152.6 (73 .4-196.2) mL/min to 109 (77-127) mL/min by the coadministration of caffeine in EMs and PMs, respectively. Consequently, the R/S ratio for urinary reco very and the partial metabolic clearance of mexiletine to N-hydroxymexileti ne were 28% lower during the coadministration of caffeine. In conclusion, d ata obtained in this study indicate that coadministration of caffeine does not lead to clinically significant changes in mexiletine plasma concentrati ons. However, results obtained suggest that CYP1A2 is involved in the forma tion of N-hydroxymexiletine.