In vivo transport of a dynorphin-like analgesic peptide, E-2078, through the blood-brain barrier: an application of brain microdialysis.
In vivo transport through the blood-brain barrier (BBB) has been demonstrated for a dynorphin-like analgesic peptide, CH3-[125I]Tyr-Gly-Gly-Phe-Leu-Arg-CH3Arg-D-Leu-NHC2H5 ( [125I]E-2078). A remarkable time-dependent increase in the distribution volume of [125I]E-2078 in the brain parenchyma separated from blood vessels and capillaries was observed during a brain perfusion. The distribution volume of [125I]E-2078 in the brain parenchyma after 20 min of perfusion was 2.18 +/- 0.09 microliters/g brain (mean +/- SE) and was significantly greater than the distribution volume of [3H]inulin (0.994 +/- 0.138 microliters/g brain), providing in vivo evidence for the penetration of [125I]E-2078 into the brain parenchyma. Brain microdialysis was carried out to collect directly the brain interstitial fluid (ISF) during the brain perfusion of [125I]E-2078. No metabolite of [125I]E-2078 in the brain ISF was found by high-performance liquid chromatographic analysis of the brain dialysate. The concentrations of [125I]E-2078 and [14C]sucrose in the brain ISF were estimated based on an in vitro evaluation of dialysis clearance. The concentration ratio of [125I]E-2078 between the brain ISF and the brain perfusate was determined to be 2.92 x 10(-1) +/- 0.50 x 10(-1) and was approximately 100 times higher than that of [14C]sucrose (2.71 x 10(-3) +/- 1.43 x 10(-3), demonstrating transport of [125I]E-2078 through the BBB in vivo. On the other hand, no remarkable difference in the cerebrospinal fluid (CSF)-to-perfusate concentration ratios of [125I]E-2078 and [14C]sucrose was observed, indicating little contribution of the blood-CSF barrier (BCSF barrier) transport to the penetration of [125I]E-2078 into the brain.
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
T
T
Terasaki
Y
Y
Deguchi
H
H
Sato
K
K
Hirai
A
A
Tsuji
D000595:Amino Acid Sequence; D000818:Animals; D001810:Blood Volume / Q000502:physiology; D001812:Blood-Brain Barrier / Q000502:physiology*; D001923:Brain Chemistry / Q000502:physiology*; D002196:Capillaries / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D003956:Dialysis; D004399:Dynorphins / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004705:Endocytosis / Q000502:physiology; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000493:pharmacokinetics*; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D014443:Tyrosine / Q000494:pharmacology
D010446:Peptide Fragments; C061285:E 2078; D014443:Tyrosine; D004399:Dynorphins