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Published online before print July 17, 2003

0031-6997/03/5503-425-461$7.00
Pharmacol Rev 55:425-461, 2003

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Impact of Drug Transporter Studies on Drug Discovery and Development

Naomi Mizuno, Takuro Niwa, Yoshihisa Yotsumoto and Yuichi Sugiyama

Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan; and Pharmacokinetics Laboratory, Mitsubishi Pharma Corporation, Chiba, Japan

Abstract
I. Introduction
II. Strategies for Drug Discovery Using Transporters
    A. Drug Delivery to Target Tissues Using Transporters
    B. Role of Brain Efflux Transporters
    C. Role of Transporters in Drug Absorption
    D. Control of Elimination by Drug Transporters (Uptake and Efflux Transporters in the Liver and Kidney)
        1. Organic Anion Transporting Polypeptide (SLC21A) Family.
        2. Organic Anion Transporter (SLC22A) Family.
        3. Organic Cation Transporter (SLC22A) Family.
        4. Multidrug Resistance-Associated Protein 2 (ABCC2).
        5. Bile Salt Export Pump (ABCB11).
III. Clinical Implications of Transporter-Mediated Drug Interactions
    A. Drug-Drug Interactions Involving Elimination
    B. Drug-Drug Interactions Involving Absorption
    C. Prediction of in Vivo Drug-Drug Interactions from in Vitro Data
IV. Possible Strategies for Drug Discovery Using Drug Transporter Inhibitors
    A. P-Glycoprotein Blockade to Overcome Multidrug Resistance
    B. P-Glycoprotein Blockade to Improve Efficacy of Human Immunodeficiency Virus Protease Inhibitors
V. Species and Gender Differences in Drug Transporters
VI. Synergistic Role of Metabolic Enzymes and Transporters
VII. The Regulation Mechanisms of Drug Transporters
    A. The Transcriptional Regulation of Transporters
    B. The Sorting and Polarization of Transporters
VIII. Polymorphisms of Drug Transporters
IX. Methods for Assessing Drug Transporter Activities in Drug Discovery
Drug transporters are expressed in many tissues such as the intestine, liver, kidney, and brain, and play key roles in drug absorption, distribution, and excretion. The information on the functional characteristics of drug transporters provides important information to allow improvements in drug delivery or drug design by targeting specific transporter proteins. In this article we summarize the significant role played by drug transporters in drug disposition, focusing particularly on their potential use during the drug discovery and development process. The use of transporter function offers the possibility of delivering a drug to the target organ, avoiding distribution to other organs (thereby reducing the chance of toxic side effects), controlling the elimination process, and/or improving oral bioavailability. It is useful to select a lead compound that may or may not interact with transporters, depending on whether such an interaction is desirable. The expression system of transporters is an efficient tool for screening the activity of individual transport processes. The changes in pharmacokinetics due to genetic polymorphisms and drug-drug interactions involving transporters can often have a direct and adverse effect on the therapeutic safety and efficacy of many important drugs. To obtain detailed information about these interindividual differences, the contribution made by transporters to drug absorption, distribution, and excretion needs to be taken into account throughout the drug discovery and development process.

Address correspondence to: Dr. Yuichi Sugiyama, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: sugiyama{at}mol.f.u-tokyo.ac.jp






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