Review
Biochemical and Molecular Pharmacological Aspects of Transporters as Determinants of Drug Disposition

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Summary:

Membrane transporters are integral membrane proteins typically having 12 transmembrane domains. Most of the SLC family transporters consist of 300–800 amino acid residues with a molecular mass of 40–90 kDa, while the corresponding values of ABC family transporters are 1,200–1,500 residues and 140–180 kDa, respectively. Each transporter has a characteristic tissue distribution and subcellular localization. I have isolated cDNAs of various transporters, including oligopeptide transporter PEPT1, monocarboxylic acid transporter MCT1 and organic cation/carnitine transporters (OCTNs), and determined their tissue distribution and subcellular localization. I have also determined the absolute expression levels of transporters to evaluate their relative contributions to drug transport in various tissues. It is important to note that expression levels of transporters can be changed under various physiological conditions and by administration of drugs. Changes in expression level, subcellular localization and functional properties can all be involved in inter-individual differences in drug pharmacokinetics. Transporters are among the key determinants of drug disposition.

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    This study was supported in part by a Grant-in-Aid for Scientific Research from MEXT (The Ministry of Education, Culture, Sports, Science, and Technology) of Japan, the “High-Tech Research Center” Project for Private Universities with matching fund subsidy from MEXT, 2004-2008, the “Open Research” Project for Private Universities with matching fund subsidy from MEXT, 2001-2005, and by grants from the Uehara Memorial Foundation, Takeda Science Foundation, and the Nagai Foundation, Tokyo.

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