Study on Regulation of Pharmacokinetics of Drugs Based on the Membrane Transport Mechanisms.

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  • TSUJI Akira
    Faculty of Pharmaceutical Sciences, Kanazawa University

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  • 薬物の生体膜輸送機構解析を基盤とした体内動態制御に関する研究

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Abstract

We succeeded the quantitative prediction of plasma and tissue concentrations of β-lactam antibitotics, insulin, pentazocine, quinolone antibacterial agents, inaperizone and digoxin by utilyzing physiologically-based pharmacokinetic models incorporated their plasma membrane transport mechanisms. Although passive diffusion, which depends on the lipid solubility, is a fundamental mechanism for the membrane transport of many of compounds, water-soluble compounds also cross cell membranes by the specialized carriermediated transport mechanisms. We have demonstrated that several drugs are transported by the tissuespecific transporters in intestinal and renal epithelial cells, hepatocytes and brain capillary endothelial cells which form the blood-brain barrier. They include oligopeptide transporter (PepT1), monocarboxylic acid transporter (MCT1), anion antiporter (AE2), organic anion transporter (Npt1), cation transporter (OCTN1 and OCTN2) and P-glycoprotein (MDR1). Most of them function for the uptakes of drugs into the cells leading to the increased permeability, others exclude drugs out of cells, thereby decreasing apparent permeability into cells. This finding demonstrates that it would be possible to expect tissue selective delivery of drugs by utilizing transporters which have different characteristics among tissues. Further mechanistic clarification and quantitative analysis of pharmacokinetic importance of such transporters will help the development of effective strategies for the site specific drug delivery.

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