The absorption, distribution, excretion, and metabolism of 14-hydroxydihydro-6β-thebainol 4-methyl ether (oxymethebanol) (I), a new strong antitussive derivative of morphine, in rats and mice were examined by radiochemical and autoradiographic methods. A peak blood level was reached within one hour after its subcutaneous administration and nearly 60 and 80% of the dose were excreted in urine during the first 6 and 12 hours, respectively. Dihydrocodeine, used for comparison, showed somewhat lower urinary excretion and relatively higher fecal excretion. Whole-body autoradiography in mice using oxymethebanol [1-3H] showed that in addition to the urinary route, which mainly contributes to the excretion, excretion into stomach and bile is also involved, in particular, at the early and later stages, respectively. At 24 hours after the administration a slight radioactivity remained only in bile and intestinal contents, showing no other organ or tissue to retain the radioactivity. Brain uptake of oxymethebanol was found to be very small except pituitary, while dihydrocodeine showed an appreciable penetration into the brain. Tissue concentrations of oxymethebanol in rats reached a maximum at around one hour after its subcutaneous administration, the concentration increasing in the following order ; kidney>liver>stomach wall>lung>diaphragm>cardiac muscle>blood>brain. Dihydrocodeine was characteristic in higher concentrations in brain and stomach wall. Most of the radioactivity in urine after subcutaneous and oral administration of oxymethebanol was due to unchanged oxymethebanol and its bound form, possibly glucuronic acid conjugate, with small amounts of 3-O-demethylated (IV), N-demethylated (V), and 3-O, N-demethylated (VII) compounds. Among rat tissue homogenates, only liver showed an activity for demethylating oxymethebanol.
