Abstract
The blood-brain barrier (BBB) permeability to morphine and morphine-6-glucuronide (M6G) is measured under identical conditions using an intravenous injection method in the rat and HPLC separation of morphine from its metabolites. The brain uptake of M6G expressed as %ID/g was 32-fold lower than that of morphine, and the BBB permeability surface area product (PS) of M6G was 57-fold lower as compared with that of morphine. Consistent with these in vivo data, the 1-octanol/buffer partition study showed the liposolubility of M6G was 187-fold lower than that of morphine. The CNS origin of M6G analgesia after peripheral administration was confirmed because the analgesia was completely blocked by naloxone, which crosses BBB, but not by naloxone methiodide, which does not enter brain from blood. In conclusion, the BBB permeability to M6G is markedly reduced as compared with morphine, consistent with the much lower lipid solubility of M6G relative to morphine.
Footnotes
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Send reprint requests to: Dr. William M. Pardridge, Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90095-1682.
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Received October 29, 1996; accepted February 12, 1997.
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This study was supported in part by a grant from the National Institute on Drug Abuse (R01-DA-06748). U.B. is supported by the Deutsche Forschungsgemeinschaft (Bi 328/4-2), and Y.-S.K. is a research fellow of the Alexander von Humboldt Foundation, Germany.
- Abbreviations used are::
- M6G
- morphine-6-β-d-glucuronide
- BBB
- blood-brain barrier
- AUC
- area under the plasma concentration-time curve
- M3G
- morphine-3-β-d-glucuronide
- CNS
- central nervous system
- ID
- injected dose
- PS
- permeability-surface area
- HSA
- human serum albumin
- RSA
- rat serum albumin
- P
- octanol/Ringer-HEPES buffer’s partition coefficient
- The American Society for Pharmacology and Experimental Therapeutics
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