Kinetic analysis of the opiate antagonist cyclofoxy in rat brain: Simultaneous infusion of active and inactive enantiomers

Journal Article · Wed Oct 31 23:00:00 EST 1990 · Journal of Pharmacology and Experimental Therapeutics; (USA)

OSTI ID:6324465

Kawai, R; Sawada, Y; Channing, M; Dunn, B; Newman, A H; Rice, K C; Blasberg, R G ^[1]

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1. National Institutes of Health, Bethesda, MD (USA)

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.

• OSTI ID: 6324465
• Journal Information: Journal of Pharmacology and Experimental Therapeutics; (USA), Journal Name: Journal of Pharmacology and Experimental Therapeutics; (USA) Vol. 255:2; ISSN JPETA; ISSN 0022-3565
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMALS
ANTIMETABOLITES
AUTONOMIC NERVOUS SYSTEM AGENTS
BETA DECAY RADIOISOTOPES
BETA-PLUS DECAY RADIOISOTOPES
BIOCHEMICAL REACTION KINETICS
BODY
BRAIN
CENTRAL NERVOUS SYSTEM
DRUGS
FLUORINE 18
FLUORINE ISOTOPES
HOURS LIVING RADIOISOTOPES
HYDROGEN COMPOUNDS
ISOMERIC TRANSITION ISOTOPES
ISOTOPE APPLICATIONS
ISOTOPES
KINETICS
LIGHT NUCLEI
MAMMALS
MATHEMATICAL MODELS
MEMBRANE PROTEINS
MEMBRANE TRANSPORT
NERVOUS SYSTEM
NEUROREGULATORS
NUCLEI
ODD-ODD NUCLEI
ORGANIC COMPOUNDS
ORGANS
PROTEINS
RADIOISOTOPES
RATS
REACTION KINETICS
RECEPTORS
RODENTS
TIME DEPENDENCE
TRACER TECHNIQUES
TRITIUM COMPOUNDS
VERTEBRATES