The lung is a preferential organ site for accumulation of lipophilic basic amine drugs, so-called pneumophilic drugs and belonging to various pharmacological classes, which can result in lung toxicity. In order to investigate the mechanism involved in such pulmonary accumulation of drugs, uptake of clonidine, used here as a prototypical basic amine drug, was characterized in cultured human lung cells. Clonidine accumulation in lung alveolar A549 cells was found to be temperature- and pH-dependent; it was saturable, with a Michaelis-Menten affinity constant (Km) value of 569.4 μM. Various pneumophilic drugs, including amitriptyline, verapamil, propranolol, chlorpromazine, imipramine, and quinidine, markedly cis-inhibited clonidine uptake in A549 cells, in a dose-dependent manner for at least some of them. They additionally trans-stimulated clonidine efflux from A549 cells, thus suggesting that they are substrates for the putative clonidine transporter. In addition to alveolar A549 cells, bronchial epithelial BEAS-2B cells as well as lung endothelial HULEC-5a cells were found to exhibit clonidine accumulation abrogated by amitriptyline, verapamil, and chlorpromazine. Taken together, these data likely provided evidence for carrier-mediated uptake of clonidine in human lung cells. This carrier, which remains to be molecularly identified, interacts with various pneumophilic drugs, suggesting that it may contribute to lung accumulation of these drugs in a notable way.
Keywords: Carrier; Clonidine; Lung; Pneumophilic drugs; Transport; Uptake.