Variability of Bioavailability and Intestinal Absorption Characteristics of Bisoprolol
Variability of Bioavailability and Intestinal Absorption Characteristics of Bisoprolol
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DOI：
10.2133/dmpk.dmpk-13-rg-017
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发表时间：
2013-12-25
影响因子：
2.1
通讯作者：
Hashimoto, Yukiya
中科院分区：
文献类型：
--
作者：
Ishida, Kazuya;Horie, Asuka;Hashimoto, Yukiya
我们以前报道过肾功能是比索洛尔药代动力学个体间差异的部分原因。本研究的目的是检查比索洛尔在常规治疗的日本患者的生物利用度(F)的变异性和该药物的肠道吸收特性。我们首先使用非线性混合效应模型分析了52名日本患者的比索洛尔血药浓度数据。我们还利用人肠上皮LS180细胞研究了比索洛尔的细胞摄取。日本患者比索洛尔的口服清除率（CL/F）与表观分布体积（V/F）呈正相关，暗示变量F。LS180细胞对比索洛尔的摄取是温度依赖性和饱和的，在奎尼丁和苯海拉明的存在下，比索洛尔的摄取显著降低。此外，溶解在酸性缓冲液中的比索洛尔的细胞摄取明显少于溶解在中性缓冲液中的比索洛尔。这些发现表明，比索洛尔的肠道吸收速率/程度是药代动力学个体间差异的另一个原因，肠上皮细胞对比索洛尔的吸收高度依赖于ph值，也是可变的。
We previously reported that renal function is partly responsible for the interindividual variability of the pharmacokinetics of bisoprolol. The aim of the present study was to examine the variability of bioavailability (F) of bisoprolol in routinely treated Japanese patients and intestinal absorption characteristics of the drug. We first analyzed the plasma concentration data of bisoprolol in 52 Japanese patients using a nonlinear mixed effects model. We also investigated the cellular uptake of bisoprolol using human intestinal epithelial LS180 cells. The oral clearance (CL/F) of bisoprolol in Japanese patients was positively correlated with the apparent volume of distribution (V/F), implying variable F. The uptake of bisoprolol in LS180 cells was temperature-dependent and saturable, and was significantly decreased in the presence of quinidine and diphenhydramine. In addition, the cellular uptake of bisoprolol dissolved in an acidic buffer was markedly less than that dissolved in a neutral buffer. These findings suggest that the rate/extent of the intestinal absorption of bisoprolol is another cause of the interindividual variability of the pharmacokinetics, and that the uptake of bisoprolol in intestinal epithelial cells is highly pH-dependent and also variable.