Determining the Time Course of CYP3A Inhibition by Potent Reversible and Irreversible CYP3A Inhibitors Using A Limited Sampling Strategy
Determining the Time Course of CYP3A Inhibition by Potent Reversible and Irreversible CYP3A Inhibitors Using A Limited Sampling Strategy
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DOI：
10.1038/clpt.2011.164
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发表时间：
2011-11-01
影响因子：
6.7
通讯作者：
Mikus, G.
中科院分区：
文献类型：
--
作者：
Katzenmaier, S.;Markert, C.;Mikus, G.
我们建立了一种新的有限采样策略来评估 CYP3A 活性，并评估可逆（伏立康唑）和不可逆（利托那韦）CYP3A 抑制的时间过程。在这项随机试验中，两组各有 8 名健康受试者，口服 CYP3A 抑制剂伏立康唑或利托那韦 9 天，并在抑制剂治疗前、抑制剂治疗期间第 1、2、3、5、8 和 9 天以及停药后第 10、11 和 12 天（3 天）服用 3 mg 咪达唑仑 (MDZ)。以溶液形式口服给药后 2 至 4 小时之间的血浆 MDZ 曲线下面积 (AUC) 与 MDZ 清除率密切相关。使用该参数，计算出伏立康唑和利托那韦的最大抑制仅发生在抑制剂开始后 48 小时（基线 MDZ 清除百分比，伏立康唑：10.6%；利托那韦：8.4%）。伏立康唑后 CYP3A 活性恢复，半衰期为 24 小时，而停药 3 天后利托那韦抑制作用仍然很强。这些发现强调了此类联合疗法的第一天和之后剂量需求的实质性和逐渐的变化。
We established a new limited sampling strategy to assess CYP3A activity and evaluated the time course of reversible (voriconazole) and irreversible (ritonavir) CYP3A inhibition. In this randomized trial, two groups, each with eight healthy participants, received CYP3A inhibitors voriconazole or ritonavir orally for 9 days, with 3 mg midazolam (MDZ) administered before the inhibitor treatment, on days 1, 2, 3, 5, 8, and 9 during inhibitor treatment, and on days 10, 11, and 12 (3 days) after discontinuation. Plasma MDZ area under the curve (AUC) between 2 and 4 h after oral administration in the form of a solution strongly correlated with MDZ clearance. Using this parameter, maximum inhibition of voriconazole and ritonavir was calculated to have occurred only 48 h after starting of the inhibitor (percentage of baseline MDZ clearance, voriconazole: 10.6%; ritonavir: 8.4%). Recovery of CYP3A activity occurred with a half-life of 24 h after voriconazole, whereas ritonavir inhibition was still strong 3 days after discontinuation. These findings underscore the substantial and gradual alterations in dose requirements in the first days of and after such combination therapies.