Drug metabolic enzymes and transporters are responsible for an important variability\nin drug disposition. The cocktail approach is a sound strategy for the simultaneous evaluation\nof several enzyme and transporter activities for a personalized dosage of medications. Recently,\nwe have demonstrated the reliability of the Geneva cocktail, combining the use of dried blood spots\n(DBS) and reduced dose of phenotyping drugs for the evaluation of the activity of six cytochromes\nand P-glycoprotein (P-gp). As part of a study evaluating potential drugâ??drug interactions between\nprobe drugs of the Geneva cocktail, the present paper focuses on the impact of cytochromes (CYP)\nprobe drugs on the disposition of fexofenadine, a P-gp test drug. In a randomized four-way\nLatin-square crossover study, 30 healthy volunteers (15 men and 15 women) received caffeine 50 mg,\nbupropion 20 mg, flurbiprofen 10 mg, omeprazole 10 mg, dextromethorphan 10 mg, midazolam 1 mg,\nand fexofenadine 25 mg alone (or as part of a previously validated combination) and all together\n(Geneva cocktail). The determination of drug concentrations was performed in DBS samples and\npharmacokinetic parameters were calculated. Fexofenadine AUC0â??8 h and Cmax decreased by 43%\n(geometric mean ratio: 0.57; CI 90: 0.50â??0.65; p < 0.001) and 49% (geometric mean ratio: 0.51; CI\n90: 0.44â??0.59; p < 0.001), respectively, when fexofenadine was administered as part of the Geneva\ncocktail in comparison to fexofenadine alone. Consequently, the apparent oral clearance (Cl/F)\nincreased 1.7-fold (CI 90: 1.49â??1.93; p < 0.001). There was no interaction between the remaining\nprobes. In conclusion, an unexpected interaction occurred between fexofenadine and one or several\nof the following substances: caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan,\nand midazolam. Further studies are necessary to elucidate the mechanism of this interaction.
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