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A recent in vitro study suggested that CYP2C8 is essential in the metabolism of desloratadine, an H1 receptor antagonist. If the proposed biotransformation mechanism takes place in vivo in humans, desloratadine could serve as a selective CYP2C8 probe substrate in drug-drug interaction studies. Glucuronide metabolites of clopidogrel and gemfibrozil act as time-dependent inhibitors of CYP2C8, but they have not been compared clinically. We conducted a randomized crossover study in 11 healthy subjects to characterize the involvement of CYP2C8 in desloratadine metabolism and to compare the CYP2C8 inhibitory strength of clopidogrel (300 and 75 mg on two following days) with that of gemfibrozil (600 mg BID for 5 days). Compared with placebo (control), clopidogrel increased the area under the plasma concentration-time curve (AUC 0-∞ ) and peak plasma concentration ( C  max ) of desloratadine to 280% ( P = 3 × 10 -7 ) and 165% ( P = 0.0006), respectively. The corresponding increases by gemfibrozil were to 462% ( P = 4 × 10 -7 ) and 174% ( P = 0.0006). Compared with placebo, clopidogrel and gemfibrozil decreased 3-hydroxyloratadine AUC 0-71h to 52% ( P = 5 × 10 -5 ) and 6% ( P = 2 × 10 -8 ), respectively. Moreover, the 3-hydroxydesloratadine:desloratadine AUC 0-71 h ratios were 21% ( P = 7 × 10 -10 ) and 1.7% ( P = 8 × 10 -11 ) of control during the clopidogrel and gemfibrozil phases. Our results confirm that CYP2C8 plays a critical role in the formation of 3-hydroxydesloratadine in humans, making desloratadine a potential CYP2C8 probe substrate. Furthermore, the findings corroborate the previous estimates that clinically relevant doses of clopidogrel cause strong CYP2C8 inhibition, whereas those of gemfibrozil almost completely inactivate the enzyme in humans.

Clopidogrel and Gemfibrozil Strongly Inhibit the CYP2C8-Dependent Formation of 3-Hydroxydesloratadine and Increase Desloratadine Exposure In Humans