Chlorphentermine binding in rat lung subcellular fractions and its displacement by desmethylimipramine.

An examination of possible mechanisms of binding interactions between drugs accumulated in the lung has been made by equilibrium dialysis using [¹⁴C]chlorphentermine (CP) in rat lung subcellular fractions (microsomal and 15,000 g and cytosol). By far the greatest CP binding was in the microsomal and 15,000 g fractions and with all isotherms, CP binding was shown to consist of a specific, saturable component and a non-specific partitioning component. Desmethylimipramine (DMI) was the most potent inhibitor of a series of compounds and was selected for detailed study. Generally, as DMI concentration was increased, CP binding decreased, however this relationship was not in accordance with simple direct competitive theory. At 5 × 10^?4 M DMI in the microsomal fraction, CP binding was initially increased with increasing CP concentration. In the 15,000 g fraction, the apparent CP affinity constant did not decrease regularly with increasing DMI concentration, the affinity constant of DMI increased with increasing DMI concentration, a Hill coefficient significantly less than unity was obtained and the binding model became increasingly untenable for higher DMI levels. It is likely that DMI and CP interact in rat lung via a cooperative mechanism involving binding-induced conformational transitions. The possible role of phospholipids in the binding of basic amines in lung is discussed.