Direct inhibition and down-regulation by uremic plasma components of hepatic uptake transporter for SN-38, an active metabolite of irinotecan, in humans

Pharm Res. 2014 Jan;31(1):204-15. doi: 10.1007/s11095-013-1153-x. Epub 2013 Aug 7.


Purpose: Clinical study has previously revealed that plasma concentration of 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of irinotecan, was higher in patients with end-stage renal failure than those with normal kidney function although SN-38 is mainly eliminated in the liver. Here, we focused on inhibition by uremic toxins of hepatic SN-38 uptake and down-regulation of uptake transporter(s) by uremic plasma in humans.

Methods: We evaluated SN-38 uptake and its inhibition by uremic toxins, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), indoxyl sulfate (Indox), hippuric acid (HA) and indole acetate (IA), with cryopreserved human hepatocytes and HEK293 cells stably expressing hepatic uptake transporters, organic anion transporting polypeptides (OATPs). We also collected plasma samples from patients with severe renal failure to examine their effects on mRNA level of OATPs in primary cultured human hepatocytes.

Results: SN-38 was taken up by hepatocytes, which showed biphasic saturation patterns. The SN-38 uptake by hepatocytes was significantly inhibited by a uremic toxin mixture including clinically relevant concentrations of CMPF, Indox, HA and IA. Kinetic analyses for OATP-mediated transport revealed that the uptake of SN-38 by OATP1B1 was the highest, followed by OATP1B3. Among the uremic toxins, CMPF exhibited most potent inhibition of OATP1B1-mediated SN-38 uptake and directly inhibited the uptake of SN-38 also in hepatocytes. In addition, gene expression of OATP1B1 and OATP1B3 in hepatocytes was significantly down-regulated by the treatment with the uremic plasma.

Conclusions: OATP1B1-mediated hepatic uptake of SN-38 was inhibited by uremic toxins, and gene expression of OATP1B1 was down-regulated by uremic plasma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biological Transport / drug effects*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / metabolism
  • Camptothecin / pharmacology
  • Cell Line
  • Down-Regulation / drug effects*
  • Female
  • HEK293 Cells
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Irinotecan
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Middle Aged
  • Organic Anion Transporters / metabolism


  • Organic Anion Transporters
  • Irinotecan
  • Camptothecin