BLOOD-BRAIN-BARRIER PERMEABILITY TO MORPHINE-6-GLUCURONIDE IS MARKEDLY REDUCED COMPARED WITH MORPHINE

The blood-brain barrier (BBB) permeability to morphine and morphine-6- glucuronide (M6G) is measured under identical conditions using an intr avenous injection method in the rat and HPLC separation of morphine fr om its metabolites, The brain uptake of M6G expressed as %ID/g was 32- fold lower than that of morphine, and the BBB permeability surface are a product (PS) of M6G was 57-fold lower as compared with that of morph ine, Consistent with these in vivo data, the 1-octanol/buffer partitio n study showed the liposolubility of M6G was 187-fold lower than that of morphine, The CNS origin of M6G analgesia after peripheral administ ration was confirmed because the analgesia was completely blocked by n aloxone, which crosses BBB, but not by naloxone methiodide, which does not enter brain from blood, In conclusion, the BBB permeability to M6 G is markedly reduced as compared with morphine, consistent with the m uch lower lipid solubility of M6G relative to morphine.