Pulmonary disposition and effects of drugs on pulmonary removal of endogenous substances

Pulmonary sequestration of drugs and other xenobiotics is known to affect respiratory and nonrespiratory functions of the lung and may be causally related to drug-induced pulmonary disease. We employed chlorphentermine (CP), an anorexic drug of amphiphilic physicochemical properties, to unravel possible mechanisms underlying drug-induced pulmonary hypertension associated with this class of drugs. In isolated perfused lungs, CP interferes with pulmonary clearance of 5-hydroxy tryptamine (5-HT) and norepinephrine. Pulmonary uptake and metabolism of 5-HT are inhibited by CP in rabbit and rat lungs. In in vitro incubations, CP is a powerful inhibitor of pulmonary monoamine oxidase activity. When pulmonary metabolism of 5-HT was blocked by pargyline, CP also inhibited pulmonary uptake of 5-HT. These effects of CP can be demonstrated in vivo in rabbits and rats during a single pulmonary passage of radio-labeled 5-HT. Not all pneumophilic drugs interfere with pulmonary clearance of 5-HT, as illustrated by the lack of effects by chlorpromazine and propranolol despite their pulmonary accumulation to a significant extent. Pulmonary accumulation of the chlorinated analogs such as chlomipramine and CP is greater than their nonchlorinated congenors, and this is in agreement with their ability to impede pulmonary clearance of 5-HT. These studies suggest that the electrophilic chlorine substitution increases the affinity of these chemicals for lung tissue, which increases the likelihood of their interference with the pulmonary disposition of 5-HT.