Osmotic blood-brain barrier opening to IgM monoclonal antibody in the rat.

Abstract

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.