AJP - Heart and Circulatory Physiology, Vol 259, Issue 4 1278-H1287, Copyright © 1990 by American Physiological Society
BBB transport and rapid tissue binding of cyclofoxy: comparison of active and inactive enantiomers
R. Kawai, Y. Sawada, M. Channing, A. H. Newman, K. C. Rice and R. G. Blasberg
Nuclear Medicine PET Section, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892.
The "rapid-phase" brain distribution of 3H-labeled enantiomers of the
opiate receptor antagonist cyclofoxy (CF), receptor active (-) and inert
(+) forms, was measured during 20- to 180-s intravenous infusion in rats.
[14C]iodoantipyrine was coinfused during these experiments to obtain a
simultaneous measure of blood flow. The influx clearance (K1) across the
blood-brain barrier (BBB) and the rapid binding equilibrium constant (Keq)
were estimated in different brain regions for both enantiomers
(2-compartmental model); a possible receptor binding process (k3) was also
examined for (-)-CF (3-compartment model). K1 (0.46-0.91 ml.min-1.g-1), the
capillary permeability-surface area product (PS; 0.75 approximately 1.4
ml.min-1.g-1) and the tissue extraction fraction (E; 0.6-0.7) were found to
be identical for both enantiomers in the nonreceptor binding model; Keq was
identical in cerebellum but larger for (-)-CF in other brain structures.
The difference in Keq between the enantiomers (2-compartment model)
correlated with the rank order of opiate receptor density observed in vitro
and in vivo. These results suggest that concomitant use of (-)-CF and
(+)-CF will be useful for in vivo receptor binding analyses.
