Suri A, Bramer S L
Department of Clinical Pharmacokinetics/Pharmacodynamics & Metabolism, Otsuka America Pharmaceutical, Inc., Rockville, MD 20850, USA.
Clin Pharmacokinet. 1999;37 Suppl 2:53-9. doi: 10.2165/00003088-199937002-00006.
In vitro results suggest that cilostazol is metabolised by cytochrome P450 (CYP) isoforms 1A2, 2D6, 3A4 and 2C19. This study was designed to evaluate the effect of concomitant administration of omeprazole (a CYP2C19 inhibitor) on the pharmacokinetics of a single 100 mg oral dose of cilostazol.
This study was conducted as a single-centre, open-label, nonrandomised, 2-period, crossover pharmacokinetic trial. A single 100 mg dose of cilostazol was administered orally on days 0 and 14. Oral omeprazole (40 mg every day) was administered on days 7 to 18.
20 healthy nonsmoking male and female volunteers.
Serial blood samples were collected before and after cilostazol administration to characterise the pharmacokinetics of cilostazol and its metabolites.
Following omeprazole coadministration, the increases in cilostazol maximum plasma concentration (Cmax) and area under the plasma concentration-time curve at time t (AUCt) were 18% (p = 0.062) and 26% (p < 0.001), respectively. For the 2 major circulating metabolites, OPC-13015 and OPC-13213, the OPC-13015 Cmax and AUCt increased by 29 and 69%, respectively (p < 0.001). However, for OPC-13213, the Cmax and AUCt decreased by 22 and 31%, respectively (p < 0.001). The plasma protein binding of cilostazol was unaffected by coadministration of omeprazole.
Coadministration of cilostazol with omeprazole resulted in an increase in the systemic exposure of cilostazol and its active metabolite, OPC-13015, by 26 and 69%, respectively. For the other active metabolite, OPC-13213, systemic exposure decreased by 31% because of inhibition of cilostazol metabolism to this metabolite. These changes in systemic exposure were well tolerated. A dose of 50 mg cilostazol twice a day should be considered during coadministration of inhibitors of CYP2C19, such as omeprazole.
体外研究结果表明，西洛他唑可被细胞色素P450（CYP）同工酶1A2、2D6、3A4和2C19代谢。本研究旨在评估同时给予奥美拉唑（一种CYP2C19抑制剂）对单次口服100 mg西洛他唑药代动力学的影响。
本研究作为一项单中心、开放标签、非随机、两阶段交叉药代动力学试验进行。在第0天和第14天口服单次100 mg西洛他唑。在第7至18天口服奥美拉唑（每日40 mg）。
20名健康的不吸烟男性和女性志愿者。
在西洛他唑给药前后采集系列血样，以表征西洛他唑及其代谢物的药代动力学。
同时给予奥美拉唑后，西洛他唑的最大血浆浓度（Cmax）和血浆浓度-时间曲线下面积（AUCt）分别增加了18%（p = 0.062）和26%（p < 0.001）。对于两种主要循环代谢物OPC-13015和OPC-13213，OPC-13015的Cmax和AUCt分别增加了29%和69%（p < 0.001）。然而，对于OPC-13213，Cmax和AUCt分别下降了22%和31%（p < 0.001）。西洛他唑的血浆蛋白结合不受奥美拉唑同时给药的影响。
西洛他唑与奥美拉唑同时给药导致西洛他唑及其活性代谢物OPC-13015的全身暴露分别增加26%和69%。对于另一种活性代谢物OPC-13213，由于西洛他唑向该代谢物的代谢受到抑制，全身暴露下降了31%。这些全身暴露的变化耐受性良好。在同时给予CYP2C19抑制剂（如奥美拉唑）期间，应考虑每日两次服用50 mg西洛他唑的剂量。
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