Species and dose differences in the accumulation of imipramine by mammalian lungs

Adult male mice, guinea pigs, rabbits, and rats were injected ip with 14C-imipramine (IP) at doses of either 10 or 50 mg/kg and killed 15 min or 12 hr later. Plasma, lung, liver, and kidney were analyzed for total radioactivity and for IP and desmethylimipramine (DMI). Neither mouse nor guinea pig lungs accumulated IP-derived 14C relative to the other tissues at either dose or time. Indeed, tissue/plasma (T/P) ratios for liver in these species exceeded those for lung. Rabbit and rat lung did not selectively accumulate radioactivity at either time point after 10 mg/kg or at 15 min after 50 mg/kg. However, 12 hr after 50 mg/kg, rabbit and rat lungs contained significantly more radioactivity than other tissues, lung T/P ratios being 3-4 times those of liver and kidney. Most of the radioactivity retained in rat lung was present as DMI (approximately 70%), whereas the three other species retained predominantly unchanged IP (60-80%). In rats, increasing the IP dose from 10 to 100 mg/kg resulted in a 10-fold increase in radioactivity in plasma, 3-fold increases in liver and kidney, and a 20-fold increase in lung. Studies with lung slices revealed that although all species avidly accumulated IP from the medium, all species but rabbit rapidly released the drug by efflux into drugfree medium. The data suggest that only rat and rabbit lung retain significant amounts of IP after administration of large doses to intact animals, and probably by different mechanisms. Rabbit lung retains mainly unchanged IP due to slow efflux of the drug from the lung whereas the rat rapidly demethylates IP to DMI and this metabolite is then retained by the lung.