Pro-inflammatory cytokines increase the permeability of paracetamol across a human endothelial-smooth muscle cell bilayer model.
Human umbilical vein endothelial cells and smooth muscle cells, cultured on either side of fixed, porous supports, were used to study the effect of pro-inflammatory cytokines on the transvascular passage of the drug paracetamol. The cellular bilayer effectively retarded the passage of the drug from the "luminal" or endothelial side, to the "tissue" or smooth muscle side of the bilayer over a 30-min period. When the cells were incubated with either IL-1beta (100 ng/l) or TNF-alpha (10 microg/l) for 4 h prior to exposure to paracetamol, the permeability of the bilayer to the drug increased to that of the control inserts without cells. In contrast, the pro-inflammatory cytokines did not affect the electrical resistance of the bilayer, indicating continued tight junctional integrity, or the passage of [3H]-inulin, an indicator of paracellular transport, or the passage of fluorescein, an indicator of passive diffusion across the cells. Together these data indicate the suitability of this syngenetic human cell co-culture model for studying factors affecting the systemic disposition of drug molecules at the level of the vascular wall. The data also indicate that the transport of paracetamol across the blood vessel wall may be greatly enhanced at sites of tissue inflammation in the systemic circulation.
Bohlin
K
K
Division of Biochemical Toxicology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
Cotgreave
I A
IA
D000082:Acetaminophen / Q000378:metabolism*; D018712:Analgesics, Non-Narcotic / Q000378:metabolism; D002463:Cell Membrane Permeability; D018920:Coculture Techniques; D016207:Cytokines / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D019793:Fluorescein / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007444:Inulin / Q000378:metabolism; D008051:Lipid Bilayers / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D014316:Tritium; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins
D018712:Analgesics, Non-Narcotic; D016207:Cytokines; D007375:Interleukin-1; D008051:Lipid Bilayers; D014409:Tumor Necrosis Factor-alpha; D014316:Tritium; D000082:Acetaminophen; D007444:Inulin; D019793:Fluorescein