title: BBB transport and rapid tissue binding of cyclofoxy: comparison of active and inactive enantiomers.
abstract: 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.
authors.affiliation: Nuclear Medicine PET Section, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: R
authors.initials: R
authors.lastname: Kawai
authors.forename: Y
authors.initials: Y
authors.lastname: Sawada
authors.forename: M
authors.initials: M
authors.lastname: Channing
authors.forename: A H
authors.initials: AH
authors.lastname: Newman
authors.forename: K C
authors.initials: KC
authors.lastname: Rice
authors.forename: R G
authors.initials: RG
authors.lastname: Blasberg
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives; D001667:Binding, Competitive; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000502:physiology*; D002560:Cerebrovascular Circulation; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D050356:Lipid Metabolism; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
chemical_list: D009271:Naltrexone; C043394:3-acetyl-6-deoxy-6-fluoronaltrexone; D000983:Antipyrine; C008135:iodoantipyrine