Drug-specificity in the perturbation of pulmonary disposition of serotonin in rabbit in vivo.
Previous work indicates that one consequence of the accumulation of several xenobiotics in the lung is compromised pulmonary disposition of 5-hydroxytryptamine (5-HT). In the present studies, we examined whether pulmonary accumulation of chlorpromazine (CPZ), propranolol (P), imipramine (IMP), and clomipramine (Cl-IMP) affected 5-HT disposition in rabbit lungs. Pulmonary extraction and metabolism of [14C]-5-HT during single pulmonary passage were examined using the reference indicator radioisotope dilution technique in male New Zealand albino rabbits. After control experiment, animals received CPZ or P (2.5, 5, or 10 mg/kg), IMP or Cl-IMP (0.25, 0.5 or 1.0 mg/kg) via the jugular vein. Pulmonary clearance was 83% of administered 5-HT. A significant proportion (28%) of total radioactivity in the bloodstream after single passage was recovered as 5-HIAA in control experiments. These values were reduced significantly to 70 and 20%, respectively upon prior administration of IMP (0.25 mg/kg). Cl-IMP was more effective in reducing these values further. CPZ and P were marginally effective at the highest dose. While prior administration of IMP and Cl-IMP resulted in pulmonary accumulation of both drugs, the latter accumulated to a significantly greater extent. These results suggest that Cl-IMP has higher affinity to the rabbit lung than IMP and may inhibit pulmonary uptake of 5-HT by competition for uptake and binding sites more than IMP.
D000818:Animals; D002746:Chlorpromazine / Q000494:pharmacology*; D002997:Clomipramine / Q000494:pharmacology*; D007099:Imipramine / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011433:Propranolol / Q000494:pharmacology*; D011817:Rabbits; D011865:Radioisotope Dilution Technique; D012701:Serotonin / Q000378:metabolism*
D012701:Serotonin; D011433:Propranolol; D002997:Clomipramine; D007099:Imipramine; D002746:Chlorpromazine