AJP - Regulatory, Integrative and Comparative Physiology, Vol 250, Issue 5 875-R883, Copyright © 1986 by American Physiological Society
Osmotic blood-brain barrier opening to IgM monoclonal antibody in the rat
E. A. Neuwelt, J. Minna, E. Frenkel, P. A. Barnett and C. I. McCormick
Pharmacokinetic parameters of iodinated monoclonal antibody (MAb) delivery
to normal rat brain were examined. The mean cerebrovascular
permeability-surface area (PA; permeability X capillary surface area) to
immunoglobulin M (IgM) MAb (mol wt 1,000,000) 10 min after infusion was
0.40 X 10(-6) S-1. When osmotic blood-brain barrier (BBB) disruption is
utilized, the PA increased to 8.36 X 10(-6) S-1. Neither intravenous nor
intracarotid MAb administration significantly affected delivery to brain.
However, osmotic BBB opening significantly (P less than 0.0005) increased
MAb uptake independent of the route of administration. After BBB opening
and intracarotid MAb the maximum concentration in brain at 1 h was 0.72%
per gram of the total administered dose. For 6 h postdisruption,
ipsilateral brain levels were 25- to 100-fold greater than in the
contralateral hemisphere or nonbarrier-disrupted controls. MAb
concentration in brain slightly decreased over 72 h (P less than 0.05).
Antibody recovered from disrupted brain retained 90% of its immunological
reactivity for at least 24 h. MAb delivery to ipsilateral brain after BBB
disruption was linear over a dose of 0.5-5.0 micrograms IgM, whereas the
percentage of the total administered dose remained unchanged. After osmotic
treatment, barrier opening was maximal to MAb delivery for 1 min with
delivery declining rapidly thereafter. The type of anesthesia used and the
administration of a thyroid-blocking agent were found to affect brain MAb
levels after BBB disruption.
