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Received for publication January 29, 2007.
Revised May 7, 2007.
Accepted for publication May 9, 2007.
This study was designed to quantitatively assess the mRNA expression of 36 important drug transporters in human jejunum, colon, liver and kidney. Expression of these transporters in human organs was compared with expression in commonly used cell lines (Caco-2, HepG2 and Caki-1) originating from these organs to assess their value as in vitro transporter system models, and was also compared with data obtained from the literature on expression in rat tissues to assess species differences. Transporters that were highly expressed in the intestine included HPT1, PEPT1, BCRP, MRP2 and MDR1 while, in the liver, OCT1, MRP2, OATP-C, NTCP and BSEP were the main transporters. In the kidney, OAT1 was expressed at the highest levels, followed by OAT3, OAT4, MCT5, MDR1, MRP2, OCT2 and OCTN2. The best agreement between human tissue and the representative cell line was observed for human jejunum and Caco-2 cells. Expression in liver and kidney ortholog cell lines was not correlated with that in the associated tissue. Comparisons with rat transporter gene expression revealed significant species differences. Our results allowed a comprehensive quantitative comparison of drug transporter expression in human intestine, liver and kidney. We suggest that it would be beneficial for predictive pharmacokinetic research to focus on the most highly expressed transporters. Our comparison of rat and human tissue will hopefully help to explain the observed species differences in in vivo models, increase understanding of the impact of active transport processes on pharmacokinetics and distribution, and improve the quality of predictions from animal studies to humans.
Key words:
absorption, drug discovery, drug distribution, drug transport, hepatic uptake, hepatobiliary transport, intestinal transport, renal transport, transporters
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