TY - JOUR T1 - Residence Times and Half-Lives of Nicotine Metabolites in Rat Brain after Acute Peripheral Administration of [2′-<sup>14</sup>C]Nicotine JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1448 LP - 1455 VL - 27 IS - 12 AU - Omar Ghosheh AU - Linda P. Dwoskin AU - Wen-Kui Li AU - Peter A. Crooks Y1 - 1999/12/01 UR - http://dmd.aspetjournals.org/content/27/12/1448.abstract N2 - The residence times of nicotine and its metabolites in rat brain after acute peripheral nicotine administration were determined. We hypothesize that nicotine metabolites will reach pharmacologically significant concentrations in brain. Cotinine, nornicotine, and norcotinine were structurally identified by dual label radiochemical and gas chromatography-mass spectrometric analysis as biotransformation products of nicotine present in rat brain after s.c. injection ofS(−)-nicotine. Two unidentified minor metabolites were also detected in brain. The half-lives in brain of nicotine metabolites were determined after a single s.c. injection of [2′-14C]-(±)nicotine (0.8 mg/kg) and analysis of radiolabeled metabolites by high pressure-liquid radiochromatography. The brain half-lives of nicotine, cotinine, and nornicotine were 52, 333, and 166 min, respectively. Peak brain concentrations of nicotine metabolites were 300, 70, and 7 nM for cotinine, nornicotine, and norcotinine, respectively. Even with potential accumulation of cotinine in brain after chronic nicotine administration, it is likely that the brain concentration 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. It is likely that nornicotine will accumulate in brain on chronic nicotine administration based on the brain half-life of this metabolite. Importantly, nornicotine is also a major alkaloidal component of tobacco. Thus, as a consequence of tobacco use, alkaloidal and metabolically formed nornicotine may reach concentrations in brain sufficient to produce pharmacological effects. The American Society for Pharmacology and Experimental Therapeutics ER -