title: Kinetic analysis of the opiate antagonist cyclofoxy in rat brain: simultaneous infusion of active and inactive enantiomers.
abstract: The opiate antagonist (-)-cyclofoxy [(-)-CF] and the receptor inert enantiomer (+)-CF were radiolabeled with 18F or 3H and administered to conscious Sprague-Dawley rats; an isotope effect was not observed. Constant i.v. infusion of both 18F-(-)-CF and 3H-(+)-CF in tracer amounts showed a marked difference in the tissue level of 18F-(-)-CF among various brain structures, whereas the values for 3H-(+)-CF were lower and much less variable. Co-infusion of unlabeled (-)-CF (1 mg/rat) did not change the tissue binding of 3H-(+)-CF in any brain structure, but reduced that of 18F-(-)-CF to the same level as 3H-(+)-CF. These results demonstrate an identical nonspecific tissue binding for (+)- and (-)-CF in vivo, and suggest that (+)-CF can be used to measure the "nonspecific" component of (-)-CF binding in brain. A nonlinear analysis of the 3H-(+)-CF data indicated the presence of both "instantaneous" and time-dependent components in nonspecific tissue binding and that nonspecific binding varied 1.5-fold in different brain structures. The combined 3H-(+)-CF and 18F-(-)-CF data were fitted to a four-compartment model, which includes parameters for capillary transport, "instantaneous" and time-dependent nonspecific tissue binding, as well as receptor association and dissociation. The receptor-association rate constant varied considerably in various structures of cerebrum (2.0-8.7 min-1), whereas receptor dissociation was estimated within a narrow range (0.12-0.17 min-1). The receptor binding potential (receptor association/dissociation) ranged between 12.7 and 56.2 and was in good agreement with previous estimates in vitro.
authors.affiliation: Nuclear Medicine Department, National Institutes of Health, Bethesda, Maryland.
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: B
authors.initials: B
authors.lastname: Dunn
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; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D005462:Fluorine Radioisotopes; D008297:Male; D008954:Models, Biological; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D009292:Narcotic Antagonists / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism; D013237:Stereoisomerism; D014316:Tritium
chemical_list: D005462:Fluorine Radioisotopes; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D014316:Tritium; D009271:Naltrexone; C043394:3-acetyl-6-deoxy-6-fluoronaltrexone