Active transport of the angiotensin-II antagonist losartan and its main metabolite EXP 3174 across MDCK-MDR1 and caco-2 cell monolayers

Br J Pharmacol. 2000 Mar;129(6):1235-43. doi: 10.1038/sj.bjp.0703150.


1. We studied the functional interaction between transport and metabolism by comparing the transport of losartan and its active metabolite EXP 3174 (EXP) across cell monolayers. 2. Epithelial layers of Caco-2 cells as well as MDR1, MRP-1 and MRP-2 overexpressing cells, in comparison to the respective wildtypes, were used to characterize the transcellular transport of losartan and EXP. 3. Losartan transport in MDCK-MDR1 and Caco-2 cells was saturable and energy-dependent with a significantly greater basolateral-to-apical (B/A) than apical-to-basolateral (A/B) flux (ratio=31+/-1 in MDCK-MDR1 and ratio 4+/-1 in Caco-2 cells). The B/A flux of losartan was inhibited by cyclosporine and vinblastine, inhibitors of P-glycoprotein and MRP. In contrast, no active losartan transport was observed in MRP-1 or MRP-2 overexpressing cells. 4. The metabolite was only transported in Caco-2 cells with a B/A-to-A/B ratio of 5+/-1, while lacking active transport in the MDR1, MRP-1 or MRP-2 overexpressing cells. The B/A flux of EXP was significantly inhibited by cyclosporine and vinblastine. 5. In conclusion, losartan is transported by P-glycoprotein and other intestinal transporters, that do not include MRP-1 and MRP-2. In contrast, the carboxylic acid metabolite is not a P-glycoprotein substrate, but displays considerably higher affinity for other transporters than losartan, that again most probably do not include MRP-1 and MRP-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2,4-Dinitrophenol / pharmacology
  • Angiotensin II / antagonists & inhibitors*
  • Animals
  • Anti-Arrhythmia Agents / metabolism*
  • Antimetabolites / pharmacology
  • Biological Transport, Active / drug effects
  • Caco-2 Cells
  • Cell Line
  • Chromatography, Liquid
  • Dogs
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology
  • Epithelium / drug effects
  • Epithelium / metabolism
  • Humans
  • Imidazoles / metabolism*
  • Kidney / drug effects
  • Kidney / metabolism
  • Kinetics
  • LLC-PK1 Cells
  • Losartan / metabolism*
  • Mass Spectrometry
  • Swine
  • Temperature
  • Tetrazoles / metabolism*


  • Anti-Arrhythmia Agents
  • Antimetabolites
  • Imidazoles
  • Tetrazoles
  • Angiotensin II
  • losartan carboxylic acid
  • Losartan
  • 2,4-Dinitrophenol