Uptake and metabolism of chlorpromazine by rat and rabbit lungs

Isolated perfused rat lung and in vitro rat and rabbit lung preparations were used to study the pulmonary uptake and metabolism of chlorpromazine (CPZ). Rat lungs were artificially ventilated and perfused via pulmonary artery with recirculating perfusate containing 1.7--180 microM 14C-CPZ. In the perfusate, 14C-CPZ-derived radioactivity declined rapidly, representing maximal pulmonary uptake at 5 min. Thereafter, the total radioactivity in the perfusate increased steadily. During the latter phase, the appearance of CPZ metabolites in the perfusate more than offset the continued decline in CPZ, suggesting metabolism of previously sequestered CPZ and a net, steady efflux of metabolites from the lung. Increasing concentration of metabolites paralleled the increase in total 14C in the perfusate. The principal metabolite was identified as CPZ-N-oxide. Biotransformation of CPZ by the perfused rat lung was temperature-sensitive and dependent on substrate concentration. Substrate saturation was apparent at 120 microM CPZ in the perfusate. In vitro incubation of 14C-CPZ with 9000g supernatant fractions of rat and rabbit lungs revealed that CPZ-metabolizing activity of rat lungs is far greater than that of rabbit lungs. In accordance with the perfusion studies, the principal pathway was N-oxidation of CPZ in the rat lung incubations. Although quantitatively much less significant, CPZ was metabolized in rabbit lung incubations, via demethylation. SKF 525-A did not inhibit CPZ metabolism by perfused or in vitro rat lung preparations, but selectively enhanced N-oxidation of CPZ. Piperonyl butoxide was without any effect. Metabolism of CPZ by rabbit lung incubations was inhibited by SKF 525-A and piperonyl butoxide. These results suggest that CPZ is metabolized by the rat lungs principally via N-oxidation by a pathway not involving cytochrome P-450; the resultant metabolite, CPZ-NO, is released into the circulation, indicating significantly lower affinity for the lung tissue than the parent compounds.