The trans-isomer of 3'-hydroxycotinine has recently been identified as a major metabolite of nicotine in urine of cigarette smokers. We, therefore, investigated the pharmacokinetics of 3'-hydroxycotinine in six male smokers after intravenous infusion of nicotine, cotinine, and 3'-hydroxycotinine. Serum concentrations of 3'-hydroxycotinine were lower than those of cotinine throughout the observation period of 60 h after infusion of nicotine or cotinine, whereas the amounts excreted in the urine were similar or higher than those of cotinine. The following means and ranges for the pharmacokinetic parameters were derived from the 3'-hydroxycotinine infusion experiment: half-life (t1/2 beta) = 5.9 (4.2-9.5) h; apparent volume of distribution (Vd) = 0.87 (0.51-1.14) l/kg; total clearance (Cl total) = 1.79 (1.08-2.59) ml/min/kg; renal clearance (Clr) = 1.31 (0.85-1.78) ml/min/kg; percentage of renal clearance (Clr/Cl total) = 75.4 +/- 12.8 (60.3-98.2). The high percentage of renal clearance suggests that further metabolization of this compound is limited. No evidence for a mutagenic activity of 3'-hydroxycotinine or of urine extracts from subjects dosed with hydroxycotinine was found with the S. typhimurium (TA 98) microsome assay.
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