ORIGINAL ARTICLE
Human Drug Transporter Gene-expressing Cells are Useful Alternatives to Predict Pharmacokinetics in Man

Naohiko Anzai1,2, Shin Wakui3, Promsuk Jutabha1,2, Tomoko Muto2, Michinari Hayashi2, Keitaro Hayashi1, Mariko Domae1, Kohsuke Uchida1, Michael F. Wempe4 and Hitoshi Endou2,5

1Dokkyo Medical University School of Medicine, Tochigi, Japan,
2Kyorin University School of Medicine, Tokyo, Japan,
3Azabu University School of Veterinary Medicine, Kanagawa, Japan,
4University of Colorado Anschutz Medical Campus, Aurora, CO, USA,
5J-Pharma Co. Ltd., Tokyo, Japan

AATEX 16(2):66-73, 2011

The liver, kidney, intestine and brain possess a wide variety of drug transporters which are very important attributes in drug disposition, safety and efficacy. onsequently, it is now well recognized that obtaining information regarding drug transporters is fundamental during novel drug development. Recent molecular cloning endeavors have identified several families (i.e. SLC22 family) of multi-specific drug transporters including organic anion and organic cation transporters (OATs/OCTs). However, genome-based drug discovery has resulted in its own set of difficulties (i.e. species differences between human and other animals) and will require animals to examine the disposition of drugs in vivo. Herein, we present an example regarding organic solute transport properties and species differences; we summarize data regarding substrate specificities among OATs/OCTs obtained from human drug transporter gene-expressing cells. The presented substrate specificity data suggest that contribution to pharmacokinetics appears to be different for each drug in vivo. Therefore, the introduction of these transporter gene-expressing cells in early drug development will lead to contributions not only in refinement, but will assist in the reduction and replacement (i.e. the three Rfs concept: Reduction, Replacement and Refinement) for alternatives to animal usage.

key words: drug transporters, transport substrates, drug-drug interaction, drug development, alternatives

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(AATEX: Altern. Animal Test. EXperiment.: Alternatives to Animal Testing and EXperimentation)