Uptake of codeine into intestinal epithelial (Caco-2) and brain endothelial (RBE4) cells.
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.
Membrane Transport Group, Biozentrum, Martin-Luther-University Halle-Wittenberg, Weinbergweg 22, D-06120 Halle, Germany.
Wiebke
W
Fischer
Jennifer
J
Bernhagen
Reinhard H H
RH
Neubert
Matthias
M
Brandsch
D001921:Brain / Q000098:blood supply*; D018938:Caco-2 Cells; D002478:Cells, Cultured; D003061:Codeine / Q000493:pharmacokinetics*; D004727:Endothelium / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D014316:Tritium
D014316:Tritium; D003061:Codeine