AJP - Heart and Circulatory Physiology, Vol 258, Issue 5 1585-H1598, Copyright © 1990 by American Physiological Society
Cerebrovascular transport of [125I]quinuclidinyl benzilate, [3H]cyclofoxy, and [14C]iodoantipyrine
Y. Sawada, S. Hiraga, C. S. Patlak, K. Ito, K. D. Pettigrew and R. G. Blasberg
Nuclear Medicine Department, National Institute of Health, National Institutes of Mental Health, Bethesda, Maryland 20892.
The transport rate constants across rat brain capillaries of a muscarinic
acetylcholine receptor antagonist, [125I]quinuclidinyl benzilate (IQNB), an
opiate receptor antagonist, [3H]cyclofoxy (CF), and a highly diffusible
blood flow indicator, [14C]iodoantipyrine (IAP), were determined by the
indicator-diffusion technique and a model that includes a distribution of
capillary transit times and a homogeneous distribution of the test compound
in the tissue parenchyma. The mean influx extraction ratio (E1) of IAP was
greater than 0.91, and E1 for CF and IQNB was 0.56-0.79 and 0.34-0.46,
respectively. The order of lipid solubility was IQNB greater than IAP
greater than CF; the apparent discrepancy (high lipid solubility and low
permeability) of IQNB was partly due to intravascular binding to plasma
protein and red blood cells. The observed initial tissue distribution
volumes (lambda 1, ml/g brain) for IQNB (0.09-0.17), CF (0.51), and IAP
(0.71) were compared with those estimated for the unbound free ligand in
blood (lambda a, ml/g brain; IQNB = 1.3-2.3, CF = 0.88, and IAP = 1.4).
These findings suggest that the binding of lipid-soluble radioligands and
drugs to plasma proteins and red blood cells can be a major determinant of
transport across the blood-brain barrier and the apparent distribution
volume of the ligand in brain tissue.
