Variability of Bioavailability and Intestinal Absorption Mechanisms of Metoprolol
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- FUKAO Miki
- Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
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- ISHIDA Kazuya
- Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
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- HORIE Asuka
- Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
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- TAGUCHI Masato
- Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
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- NOZAWA Takashi
- Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
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- INOUE Hiroshi
- Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
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- HASHIMOTO Yukiya
- Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
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Abstract
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.<br>
Journal
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- Drug Metabolism and Pharmacokinetics
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Drug Metabolism and Pharmacokinetics 29 (2), 162-167, 2014
The Japanese Society for the Study of Xenobiotics
