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College of Pharmacy and Center for Toxicology, University of
Kentucky
The time course of nicotine metabolite appearance in brain from 5 min-18 hr after subcutaneous administration of
S-(
)-[3H-N-methyl]nicotine was
determined. Results demonstrated that metabolite appearance in brain
was greatest at 4 hr postadministration, whereas levels of nicotine
were greatly diminished at this time point. For determination of
N-demethylated metabolites,
(±)-[2
-14C]nicotine was administered subcutaneously to
rats, and the presence of nicotine and nicotine metabolites in brain
supernatant was determined 4 hr postadministration. Using
high-performance liquid radiochromatographic analysis, nicotine and
three nicotine metabolites (cotinine, nornicotine, and norcotinine)
were identified in brain, together with a fourth minor, unidentified
metabolite. After subcutaneous administration of
S-()-[G-3H]cotinine, significant amounts of
cotinine were found in brain over an 18-hr postadministration period;
however, no cotinine metabolites were detected. Therefore, cotinine is
able to pass the blood-brain barrier and access the central nervous
system, but is not biotransformed in brain. Thus, this is the first
report of norcotinine as a central nervous system nicotine metabolite. Data indicate that norcotinine detected in brain after peripheral nicotine administration most likely originates from 5-C-oxidation of
brain nornicotine, rather than from N-demethylation of
cotinine, as occurs peripherally. Because peripheral biotransformation
of nicotine to nornicotine is a minor pathway, the relatively high levels of nornicotine found in brain after peripheral nicotine administration suggest that nornicotine is formed via
oxidative N-demethylation of nicotine locally in brain.
Nornicotine is pharmacologically active; thus, its presence in brain
after peripheral nicotine administration indicates that nornicotine may
contribute to the neuropharmacological effects of nicotine and tobacco
use.
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