Variability of Bioavailability and Intestinal Absorption Mechanisms of Metoprolol
Variability of Bioavailability and Intestinal Absorption Mechanisms of Metoprolol
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DOI：
10.2133/dmpk.dmpk-13-rg-057
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发表时间：
2014-04-25
影响因子：
2.1
通讯作者：
Hashimoto, Yukiya
中科院分区：
文献类型：
--
作者：
Fukao, Miki;Ishida, Kazuya;Hashimoto, Yukiya
我们以前曾报道过，年龄和/或细胞色素P450 2D 6多态性是导致美托洛尔全身清除率（CL）和生物利用度（F）个体间差异的原因。本研究的目的是评价常规治疗的日本患者中美托洛尔的F的残留变异性，并使用人肠上皮LS 180细胞研究药物的肠吸收机制。我们首先使用非线性混合效应模型重新分析了34例日本患者的美托洛尔血药浓度数据。美托洛尔的口服清除率（CL/F）与表观分布容积（V/F）呈正相关，提示F存在残差变异性。LS 180细胞对美托洛尔的摄取显著降低，细胞外介质pH值的酸化，并依赖于温度和细胞内的pH值。此外，美托洛尔的细胞摄取是饱和的，并显着降低在存在疏水性阳离子药物，如苯海拉明，普鲁卡因胺，比索洛尔，奎尼丁。这些结果表明，F的残留变异性是美托洛尔个体间药代动力学变异性的原因之一，并且不仅系统前首过代谢的个体间变异性，而且肠道吸收的个体间变异性可能是药物的变量F的原因。
We previously reported that aging and/or cytochrome P450 2D6 polymorphism are responsible for the interindividual variability in the systemic clearance (CL) and bioavailability (F) of metoprolol. The aim of the present study was to evaluate the residual variability of F of metoprolol in routinely treated Japanese patients and to investigate the intestinal absorption mechanism of the drug using human intestinal epithelial LS180 cells. We first re-analyzed the blood concentration data for metoprolol in 34 Japanese patients using a nonlinear mixed effects model. The oral clearance (CL/F) of metoprolol was positively correlated with the apparent volume of distribution (V/F), suggesting the residual variability of F. The uptake of metoprolol into LS180 cells was significantly decreased by the acidification of extracellular medium pH, and was dependent on temperature and intracellular pH. Furthermore, the cellular uptake of metoprolol was saturable, and was significantly decreased in the presence of hydrophobic cationic drugs such as diphenhydramine, procainamide, bisoprolol, and quinidine. These findings indicate that residual variability of F is one of the causes of the interindividual pharmacokinetic variability of metoprolol, and that the interindividual variability of not only presystemic first-pass metabolism, but also intestinal absorption, may be responsible for the variable F of the drug.