Residence times and half-lives of nicotine metabolites in rat brain after acute peripheral administration of [2 '-C-14] nicotine

The residence times of nicotine and its metabolites in rat brain after acut e peripheral nicotine administration were determined. We hypothesize that n icotine metabolites will reach pharmacologically significant concentrations in brain. Cotinine, nornicotine, and norcotinine were structurally identif ied by dual label radiochemical and gas chromatography-mass spectrometric a nalysis as biotransformation products of nicotine present in rat brain afte r s.c. injection of S(-)-nicotine. Two unidentified minor metabolites were also detected in brain. The half-lives in brain of nicotine metabolites wer e determined after a single s.c. injection of [2'-C-14]-(+/-)nicotine (0.8 mg/kg) and analysis of radiolabeled metabolites by high pressure-liquid rad iochromatography. The brain half-lives of nicotine, cotinine, and nornicoti ne were 52, 333, and 166 min, respectively. Peak brain concentrations of ni cotine metabolites were 300, 70, and 7 nM for cotinine, nornicotine, and no rcotinine, respectively. Even with potential accumulation of cotinine in br ain after chronic nicotine administration, it is likely that the brain conc entration of cotinine will be insufficient to produce neuropharmacological effects resulting from activation of nicotinic receptors to induce dopamine release. Conversely, the concentration of nornicotine in brain after acute nicotine approaches the range found to be neuropharmacologically active. I t is likely that nornicotine will accumulate in brain on chronic nicotine a dministration based on the brain half-life of this metabolite. Importantly, nornicotine is also a major alkaloidal component of tobacco. Thus, as a co nsequence of tobacco use, alkaloidal and metabolically formed nornicotine m ay reach concentrations in brain sufficient to produce pharmacological effe cts.