Effects of chlorphentermine and phentermine on the pulmonary disposition of 5-hydroxytryptamine in the rat in vivo.

This study was designed to examine whether chlorphentermine (CP) affects pulmonary disposition of 5-hydroxytryptamine (5-HT) in rat in vivo. Further, the effects of CP were compared with those of phentermine (P), the nonchlorinated congener. The right jugular vein and left carotid artery of male Sprague-Dawley rats were cannulated to the level of the superior caval vein and ascending aorta, respectively. After 10 min of stabilization, 0.3 ml fresh saline solution containing 150 micrograms indocyanine green and a mixture of labeled and unlabeled 5-HT was injected into the jugular vein, and arterial blood samples were collected for 20 s. Pulmonary extraction of 5-HT during a single pass was inversely proportional to the injected dose, ranging from 67% cf injected dose for a 2.6 nmol dose to 30% for a 130 nmol dose, indicating a saturable pulmonary uptake for 5-HT. In order to compare the effect of CP and P on pulmonary disposition of 5-HT, 2.6 nmol [14C]-5-HT was employed for in vivo single-pass experiments. Each animal was used for 2 in vivo single-pass experiments. After the first experiment, which served as a control, animals received an indicated dose of CP or P, to commence the second "drug-treated" in vivo experiment. Pulmonary clearance of 5-HT was inhibited by prior administration of CP (1 mg/kg) by 42%, whereas at the highest dose (20 mg/kg) P inhibited 5-HT clearance by only 25%. Pulmonary accumulation of CP was greater than P at higher doses, and the inhibition of 5-HT clearance correlated with the pulmonary accumulation of these drugs. In addition to the in vivo demonstration of the CP inhibition of pulmonary clearance of 5-HT in the rat, these studies also demonstrate a higher affinity of the lung tissue for CP than for P and a greater propensity for the impairment of pulmonary 5-HT clearance.