Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Drug Metab Dispos. 2019 Apr;47(4):377-385. doi: 10.1124/dmd.118.084665. Epub 2019 Jan 10.
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) and peak plasma concentration ( ) of desloratadine to 280% ( = 3 × 10) and 165% ( = 0.0006), respectively. The corresponding increases by gemfibrozil were to 462% ( = 4 × 10) and 174% ( = 0.0006). Compared with placebo, clopidogrel and gemfibrozil decreased 3-hydroxyloratadine AUC to 52% ( = 5 × 10) and 6% ( = 2 × 10), respectively. Moreover, the 3-hydroxydesloratadine:desloratadine AUC ratios were 21% ( = 7 × 10) and 1.7% ( = 8 × 10) 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.
最近的一项体外研究表明，CYP2C8 是去氯雷他定（一种 H1 受体拮抗剂）代谢所必需的。如果提议的生物转化机制在人体内发生，那么去氯雷他定可以作为药物相互作用研究中选择性 CYP2C8 探针底物。氯吡格雷和吉非贝齐的葡萄糖醛酸代谢物是 CYP2C8 的时间依赖性抑制剂，但尚未在临床上进行比较。我们在 11 名健康受试者中进行了一项随机交叉研究，以表征 CYP2C8 在去氯雷他定代谢中的作用，并比较氯吡格雷（随后两天各 300mg 和 75mg）与吉非贝齐（5 天内每天 2 次 600mg）对 CYP2C8 的抑制强度。与安慰剂（对照）相比，氯吡格雷使去氯雷他定的血浆浓度-时间曲线下面积（AUC）和峰血浆浓度（ ）增加了 280%（ = 3 × 10）和 165%（ = 0.0006）。吉非贝齐的相应增加分别为 462%（ = 4 × 10）和 174%（ = 0.0006）。与安慰剂相比，氯吡格雷和吉非贝齐使 3-羟基去氯雷他定 AUC 降低了 52%（ = 5 × 10）和 6%（ = 2 × 10）。此外，在氯吡格雷和吉非贝齐阶段，3-羟去氯雷他定：去氯雷他定 AUC 比值分别为对照的 21%（ = 7 × 10）和 1.7%（ = 8 × 10）。我们的研究结果证实，CYP2C8 在人类中 3-羟去氯雷他定的形成中起着关键作用，使去氯雷他定成为潜在的 CYP2C8 探针底物。此外，这些发现证实了先前的估计，即临床相关剂量的氯吡格雷会导致强烈的 CYP2C8 抑制，而吉非贝齐在人类中几乎完全使该酶失活。
