The binding of chlorphentermine (461789) to phospholipids in alveolar lavage materials and lung cells was studied in rats. In a preliminary experiment, lungs removed from male Sprague-Dawley-rats were lavaged. The lavage fluid was incubated with 10 millimolar chlorphentermine and 50 micromolar 1-anilino-8-naphthalene-sulfonate (ANS). After differential centrifugation, the extent of binding of chlorphentermine to phospholipids in the various lavage fractions was determined using a fluorometric assay based on ANS. Chlorphentermine was bound equally to phospholipids in all fractions. Male Sprague-Dawley-rats were injected with 25mg/kg carbon-14 labeled chlorphentermine daily for 3 days. They were killed 24 hours after the last dose and the lungs were removed and lavaged. The extent of chlorphentermine/phospholipid binding in the cell free whole lavage fluid, alveolar macrophages, type-II cells, and other pneumocytes was determined. Chlorphentermine was bound to phospholipids in whole lavage fluid in a 1:100 mole ratio. Chlorphentermine bound to phospholipids in the alveolar macrophages, type-II cells, and other lung lung cells in mole ratios of 1:18, 1:33, and 1:333, respectively. The authors conclude that chlorphentermine binds to pulmonary surfactant phospholipids in- vitro. In-vivo, it binds to phospholpids in at least three different compartments: acellular lavage fluid, alveolar macrophages, and type-II cells. The interaction of chlorphentermine with phosphoplipids may impair phospholipid degradation resulting in phospholipidosis in surfactant materials and alveolar macrophages.