DISTRIBUTION OF MORPHINE 6-GLUCURONIDE AND MORPHINE ACROSS THE BLOOD-BRAIN-BARRIER IN AWAKE, FREELY MOVING RATS INVESTIGATED BY IN-VIVO MICRODIALYSIS SAMPLING

Microdialysis was used to sample morphine 6-glucuronide (M6G) and morp hine in striatal extracellular fluid after systemic administration in awake, freely moving rats. Morphine or M6G (25-67 mu mol/kg) was given subcutaneously, and blood and striatal dialysate were sampled repeate dly during 120 min. Blood samples were obtained by indwelling catheter s in the inferior vena cava, Opiates in serum or brain dialysate were analyzed with high-performance liquid chromatography. The functional i ntactness of the blood-brain barrier was verified by the use of sodium technetate ((NaTcO4)-Tc-99m). The fractional penetration into the bra in of morphine and M6G was approximately 350- and 90-fold higher than that of (NaTcO4)-Tc-99m, respectively, with a relative difference in t he transfer of morphine and M6G of about 4. No hydrolysis of M6G to mo rphine was detected. Striatal dialysate-to-serum ratios of M6G did not differ after 25 or 67 mu mol/kg. Serum AUC(0-120min) was 10 times hig her for M6G than for morphine. This reflects both a smaller volume of distribution (V-d) for M6G and a decreased rate of elimination compare d with morphine. The median t(1/2) from serum was 36 and 32 min for mo rphine and M6G, respectively. The striatal dialysate AUC(0-120min) of M6G was 2.9 times greater than that of morphine after an equimolar sub cutaneous dose. Dialysate t(max) was delayed approximately 40 min rela tive to serum t(max) for both drugs, and the median t(1/2) from the di alysate was 82 and 48 min for M6G and morphine, respectively. These re sults represent direct evidence for the penetration of M6G into the br ain after systemic administration to living rats.