SPECIES AND DOSE DIFFERENCES IN THE ACCUMULATION OF IMIPRAMINE BY MAMMALIAN LUNGS

  • 1 January 1981
    • journal article
    • research article
    • Vol. 9  (4) , 322-328
Abstract
Adult male mice, guinea pigs, rabbit and rats were injected i.p. with 14C-imipramine (IP) at doses of 10 or 50 mg/kg and killed 15 min or 12 h later. Plasma, lung, liver and kidney were analyzed for total radioactivity and for IP and demethylimipramine (DMI). Mouse and guinea pig lungs did not accumulate IP-derived 14C relative to the other tissues at either dose or time. Tissue/plasma (T/P) ratios for liver in the 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. Twelve h after 50 mg/kg, rabbit and rat lungs contained significantly more radioactivity than other tissues, lung T/P ratios were 3-4 times those of liver and kidney. Most of the radioactivity retained in rat lung was present as DMI (.apprx. 70%); the 3 other species retained predominantly unchanged IP (60-80%). In rats, increasing the IP dose from 10 to 100 mg/kg caused 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. 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 but the rat rapidly demethylates IP to DMI and this metabolite is then retained by the lung.