Document Detail


Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines.
MedLine Citation:
PMID:  17496207     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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, whereas, 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. We hope that our comparison of rat and human tissue will 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.
Authors:
Constanze Hilgendorf; Gustav Ahlin; Annick Seithel; Per Artursson; Anna-Lena Ungell; Johan Karlsson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-05-11
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  35     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2007 Aug 
Date Detail:
Created Date:  2007-07-20     Completed Date:  2007-11-02     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1333-40     Citation Subset:  IM    
Affiliation:
Discovery Drug Metabolism and Pharmacokinetics & Bioanalytical Chemistry, AstraZeneca Research & Development, Mölndal, Sweden. constanze.hilgendorf@astrazeneca.com
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / genetics
Aged
Aged, 80 and over
Animals
Caco-2 Cells
Cell Line, Tumor
Colon / metabolism
Female
Gene Expression Profiling*
Humans
Intestines / metabolism*
Jejunum / metabolism
Kidney / metabolism*
Liver / metabolism*
Male
Membrane Transport Proteins / genetics*
Middle Aged
Principal Component Analysis
Rats
Reverse Transcriptase Polymerase Chain Reaction
Chemical
Reg. No./Substance:
0/ATP-Binding Cassette Transporters; 0/Membrane Transport Proteins

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