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• W2324686543 abstract "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 implicated in the formation of N-hydroxymexiletine, the major metabolite of mexiletine. Therefore, the objective of this study was to assess the effects of a clinically relevant dosage of caffeine on the stereoselective disposition of mexiletine. Fourteen healthy volunteers-10 extensive metabolizers (EMs) and 4 poor metabolizers (PMs) of CYP2D6-received a single 200 mg oral dose of 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 parameters were estimated. Although the total clearance of mexiletine was not significantly altered by the coadministration of caffeine in EMs and PMs, a stereoselective decrease (16% in EMs and 14% in PMs) in the urinary recovery of N-hydroxymexiletine from the R-(-)-enantiomer was observed. Also, the partial metabolic clearance of R-(-)-mexiletine to N-hydroxymexiletine glucuronide 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 recovery and the partial metabolic clearance of mexiletine to N-hydroxymexiletine were 28% lower during the coadministration of caffeine. In conclusion, data obtained in this study indicate that coadministration of caffeine does not lead to clinically significant changes in mexiletine plasma concentrations. However, results obtained suggest that CYP1A2 is involved in the formation of N-hydroxymexiletine." @default.
• W2324686543 created "2016-06-24" @default.
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• W2324686543 date "1999-04-01" @default.
• W2324686543 modified "2023-09-27" @default.
• W2324686543 title "Stereoselective Disposition of the Antiarrhythmic Agent Mexiletine During the Concomitant Administration of Caffeine" @default.
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• W2324686543 doi "https://doi.org/10.1097/00007691-199904000-00009" @default.
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