Itraconazole greatly increases plasma concentrations and effects of felodipine
Itraconazole greatly increases plasma concentrations and effects of felodipine
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DOI：
10.1016/s0009-9236(97)90191-0
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发表时间：
1997-04-01
影响因子：
6.7
通讯作者：
Neuvonen, PJ
中科院分区：
文献类型：
--
作者：
Jalava, KM;Olkkola, KT;Neuvonen, PJ
背景：非洛地平是一种二氢吡啶类钙拮抗剂，广泛由 CYP3A4 代谢。伊曲康唑与 CYP3A4 的一些底物（例如特非那定、三唑仑和洛伐他汀）有强烈的相互作用；因此，揭示伊曲康唑与非洛地平可能的相互作用非常重要。方法：采用双盲、随机、两阶段交叉设计来研究非洛地平与伊曲康唑之间的相互作用。 9 名健康志愿者每天口服 200 毫克伊曲康唑或安慰剂，持续 4 天。第 4 天，每人口服 5 毫克非洛地平。测定非洛地平和伊曲康唑的血浆浓度，并测量长达 32 小时的收缩压和舒张压以及心率。结果：平均而言，伊曲康唑使非洛地平的血浆峰值浓度 (C-max) 增加近八倍 (p < 0.001)、非洛地平浓度-时间曲线下面积 [AUC(0-32) 和 AUC(0-无穷大)]约六倍(p < 0.001)，消除半衰期两倍(p < 0.05)。在九名受试者中的七名中，即使没有伊曲康唑，非洛地平的 C-max 也低于伊曲康唑阶段的 32 小时浓度。伊曲康唑阶段的血压下降和心率的增加明显大于安慰剂阶段。结论：伊曲康唑大大增加了口服非洛地平的血浆浓度和作用。在非洛地平的首过和消除阶段对 CYP3A4 的抑制似乎是观察到的相互作用的机制。应避免伊曲康唑和其他一些唑类抗真菌药与非洛地平和其他二氢吡啶类钙拮抗剂同时使用或相应减少剂量。
Background: Felodipine, a dihydropyridine calcium antagonist, is extensively metabolized by CYP3A4. Itraconazole strongly interacts with some of the substrates of CYP3A4 (e.g., terfenadine, triazolam and lovastatin); hence it is important to uncover the possible interaction of itraconazole with felodipine.Methods: A double-blind, randomized, two-phase crossover design was used to investigate the interaction between felodipine and itraconazole. Nine healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each ingested a single 5 mg oral dose of felodipine. Plasma concentrations of felodipine and itraconazole were determined and systolic and diastolic blood pressures and heart rate were measured up to 32 hours.Results: On average, itraconazole increased the peak plasma concentration (C-max) of felodipine nearly eightfold (p < 0.001), the areas under the felodipine concentration-time curve [AUC(0-32) and AUC(0-infinity)] about sixfold (p < 0.001), and the elimination half-life twofold (p < 0.05). In seven of the nine subjects, even the C-max of felodipine was lower without itraconazole than the 32-hour concentrations during the itraconazole phase. The decreases in blood pressure and the increases in heart rate were significantly greater during the itraconazole phase than during the placebo phase.Conclusions: Itraconazole greatly increases plasma concentrations and effects of oral felodipine. The inhibition of CYP3A4 during the first-pass and elimination phases of felodipine seems to be the mechanism of the observed interaction. The concomitant use of itraconazole and some other azole antifungals with felodipine and other dihydropyridine calcium antagonists should be avoided or their doses should be reduced accordingly.