Delivery of human interferon-alpha to brain by transient osmotic blood-brain barrier modification in the rat.
Pharmacokinetic parameters of human lymphoblastoid interferon (IFN-alpha) delivery to normal rat brain were examined. IFN-alpha concentrations in brain parenchyma could only be detected 120 min after its intravascular administration, and were 0.003% per gram of the administered dose. The mean cerebrovascular permeability-surface area (permeability x surface area) product to IFN, 120 min after infusion, was 0.35 x 10(-6) sec-1, which is not significantly different from zero. Neither i.v. nor intracarotid IFN-alpha administration significantly affected delivery to brain. Intrathecal administration of IFN-alpha, via the cisterna magna, resulted in undetectable concentrations in brain tissue and plasma at 30 and 60 min. However, osmotic blood-brain barrier opening significantly increased IFN-alpha delivery to brain after its carotid administration. A maximum concentration of 0.18% per gram of the total administered dose was achieved at 120 min, and the cerebrovascular permeability-surface area was increased to 30.8 x 10(-6) sec-1. Intracerebral IFN-alpha concentrations did not decline significantly during the 240 min study. Osmotic blood-brain barrier opening increased the area under the brain concentration vs. time curve, measured between 30 and 240 min, from 0.012 x 10(6) U.min/g, in controls, to 1.24 x 10(6) U.min/g, at least 100-fold. This study indicates that osmotic blood-brain barrier opening significantly increases the delivery of IFN-alpha into brain, and that delivered remains within the brain for many hours.
Greig
N H
NH
Laboratory of Neurosciences, National Institute on Aging, Bethesda, Maryland.
Fredericks
W R
WR
Holloway
H W
HW
Soncrant
T T
TT
Rapoport
S I
SI
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D006801:Humans; D007370:Interferon Type I / Q000097:blood / Q000493:pharmacokinetics*; D007700:Kinetics; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013395:Sucrose / Q000493:pharmacokinetics
D007370:Interferon Type I; D013395:Sucrose