Uptake of codeine into intestinal epithelial (Caco-2) and brain endothelial (RBE4) cells

Eur J Pharm Sci. 2010 Sep 11;41(1):31-42. doi: 10.1016/j.ejps.2010.05.010. Epub 2010 May 25.


Orally administered codeine has to permeate both the intestinal and the blood-brain barrier in order to act as analgesic and cough suppressant. In this study we characterized the uptake of codeine at intestinal epithelial (Caco-2) and brain endothelial (RBE4) cells. At both cell types, uptake of [(3)H]codeine was independent of an inwardly directed Na(+) gradient. Uptake was, however, strongly stimulated by an outwardly directed H(+) gradient and inhibited by the protonophore FCCP. [(3)H]Codeine uptake into Caco-2 cells was strongly temperature dependent. In the presence of excess amounts of unlabeled codeine, the uptake was inhibited by up to 87% (Caco-2) or 94% (RBE4), respectively. Synthetic opioids and some non-opioid organic cations like propranolol, pyrilamine and quinidine potently inhibited [(3)H]codeine uptake. Several prototype substrates of known transporters for amino acids, neurotransmitters and organic cations were ineffective. Our data are consistent with a hypothetic saturable, H(+)-dependent (antiport) mechanism not yet identified on a molecular level. The pH dependence of codeine uptake and its intracellular accumulation can partially also be explained by a model comprising diffusional membrane permeation of unionized species of codeine followed by codeine sequestration into acidic vesicles and distribution into cellular lipids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / blood supply*
  • Caco-2 Cells
  • Cells, Cultured
  • Codeine / pharmacokinetics*
  • Endothelium / cytology
  • Endothelium / metabolism*
  • Humans
  • Intestinal Mucosa / metabolism*
  • Tritium


  • Tritium
  • Codeine