Hydrogen peroxide-induced epithelial damage increases terbutaline transport in guinea-pig tracheal wall: implications for drug delivery.
An isolated vagus nerve-tracheal tube preparation from guinea-pig was treated intraluminally with hydrogen peroxide (H2O2) at various concentrations. Exposure to, 100 mmol/L H2O2 for 20 min was chosen for further experiments since it appeared to cause selective damage to the epithelium. Thus the subepithelial layers of the tracheal wall appeared intact as judged by light microscopic examination. The response to nerve stimulation (increase in intratracheal pressure) was attenuated by only about 20%. Terbutaline administration into the tracheal lumen caused a concentration-dependent inhibition of the response to nerve stimulation. In tracheal preparations pretreated with 100 mmol/L H2O2 there was a 20-fold decrease in the EC50 for terbutaline. The EC50 for terbutaline added to the external medium was not changed by the H2O2 pretreatment. The efflux of 3H-terbutaline from the tracheal lumen into the external medium was three times higher in H2O2-treated than in control preparations. It is concluded that in the H2O2-damaged epithelium the absorption of terbutaline is enhanced resulting in a better availability of the drug in the smooth muscle layer after intraluminal administration.
Jeppsson
A B
AB
Research and Development Department, AB Draco Lund, Sweden.
Sundler
F
F
Luts
A
A
Waldeck
B
B
Widmark
E
E
D000818:Animals; D001692:Biological Transport; D002217:Carbachol / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006861:Hydrogen Peroxide; D066298:In Vitro Techniques; D008297:Male; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism; D013726:Terbutaline / Q000493:pharmacokinetics*; D013997:Time Factors; D014132:Trachea / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D014136:Tracheitis / Q000139:chemically induced / Q000378:metabolism*; D014316:Tritium; D014630:Vagus Nerve / Q000502:physiology
D014316:Tritium; D002217:Carbachol; D006861:Hydrogen Peroxide; D013726:Terbutaline