DISTRIBUTION OF MORPHINE 6-GLUCURONIDE AND MORPHINE ACROSS THE BLOOD-BRAIN-BARRIER IN AWAKE, FREELY MOVING RATS INVESTIGATED BY IN-VIVO MICRODIALYSIS SAMPLING
Ta. Aasmundstad et al., DISTRIBUTION OF MORPHINE 6-GLUCURONIDE AND MORPHINE ACROSS THE BLOOD-BRAIN-BARRIER IN AWAKE, FREELY MOVING RATS INVESTIGATED BY IN-VIVO MICRODIALYSIS SAMPLING, The Journal of pharmacology and experimental therapeutics, 275(1), 1995, pp. 435-441
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.