Expression of Thirty-six Drug Transporter Genes in Human Intestine, Liver, Kidney, and Organotypic Cell Lines

Abstract

ABSTRACT: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.

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

“…MRP5 ABCC5 N.R. Jejunum, ileum > duodenum [28] Jejunum = colon [14] Jejunum [20] Small intestine [21,32] Colon [28,32] N.R.…”

“…However, it is generally accepted that the absorptive transporters ASBT, MRP3, MCT1, OATP2B1 and OSTa/b have moderate to high intestinal expression levels. [12,[14][15][16]18,20,21,29,32,33,36,39,40] The three known intestinal exsorptive transporters for organic anions (BCRP, MRP2 and OSTa/b) all have relatively high expression levels -especially BCRP has a high intestinal expression compared with other tissues. [14,16,18,20,21,23,39] A high transporter expression level is likely indicative of an important role in the absorption or elimination of endogenous and exogenous substances.…”

“…The intestinal expression of the absorptive transporter OATP1A2 is less evident. Two scientific papers have suggested that OATP1A2 is expressed at mRNA levels in the small intestine, and this transporter has also been [12,13] Jejunum > colon [14] Ileum [15] Ileum > duodenum [13] BCRP ABCG2 Ex Ileum > duodenum, colon [16] Duodenum > ileum > colon [17] Jejunum > colon [14,18] Duodenum [19] Jejunum [20] Small intestine [21] Duodenum = ileum = colon [22] Small intestine and colon [23] MCT1 SLC16A1 Ab Colon > duodenum > ileum [16] Colon > duodenum [24] Colon > jejunum [18] Colon > ileum [25] Jejunum = colon [15] Small intestine [21,26] Colon > ileum > jejunum [24] Colon [25] MCT3 SLC16A8 N.R. N.R.…”

“…Jejunum > colon [14] Colon > ileum, not in jejunum [24] MRP1 ABCC1 Ab Jejunum = ileum = colon [27] Jejunum, ileum > duodenum [28] Jejunum = colon [14] Duodenum [19] Jejunum [20] Small intestine [21,29] Colon [29,30] Small intestine and colon [31] Too low expression in jejunum, ileum and colon for protein determination [29] MRP2 ABCC2 Ex Jejunum > ileum > > colon [27] Duodenum > ileum > > colon [32] Duodenum = ileum > colon [16] Jejunum, ileum > duodenum [28] Duodenum > > colon [33] Jejunum > colon [18] Duodenum [19] Jejunum [16,20] Small intestine [21] Jejunum > ileum = colon [27] MRP3 ABCC3 Ab Colon > Ileum = duodenum [16] Jejunum, ileum > duodenum [28] Colon > jejunum [18] Duodenum [19] Jejunum [16,20] Small intestine [21,32] Colon [28,32] Small intestine and colon [29] MRP4 ABCC4 N.R. Jejunum, ileum > duodenum [28] Jejunum = colon [14] Jejunum [20] Small intestine [21,32] Colon [28,32] N.R. MRP5 ABCC5 N.R.…”

“…Jejunum, ileum > duodenum [28] Jejunum [20] Small intestine [21,34] Colon [34] Small intestine and colon [34] OATP1A2 (OATP-A) SLCO1A2 Ab Duodenum [19] Small intestine [21] NOT in duodenum, ileum or colon [12] NOT in jejunum or colon [14] NOT in small intestine [35] Duodenum [19] OATP2B1 (OATP-B) SLCO2B1 Ab Duodenum = ileum = colon [12,16] Jejunum = colon [14] Jejunum > colon [18] Duodenum [19] Jejunum [36] Small intestine [21,35] Small intestine [37] OATP3A1_v1 (OATP-D) SLCO3A1 N.R. Jejunum [14] Small intestine and colon [35,36] NOT in colon [14] N.R.…”