3’-hydroxycotinine

Tuomi T, Johnsson T, Reijula K. 1999. Analysis of nicotine, 3-hydroxycotinine, cotenine, and caffeine in urine of passive smokers by HPLC-tandem mass spectrometry. Clin Chem 45 2164. 

Although on average about 70-80% of nicotine is metabolized via the cotinine pathway in humans, only 10-15% of nicotine absorbed by smokers appears in the urine as unchanged cotinine (Benowitz et al. 1994). Six primary metabolites of cotinine have been reported in humans 3 -hydroxycotinine (McKennis et al. 1963 Neurath et al. 1987), 5 -hydroxycotinine (also called allohydroxycotinine) (Neurath 1994), which exists in tautomeric equilibrium with the open chain derivative... 

Quantitative aspects of the pattern of nicotine metabolism have been elucidated fairly well in people (Fig. 4). Approximately 90% of a systemic dose of nicotine can be accounted for as nicotine and metabolites in urine (Benowitz et al. 1994). Based on studies with simultaneous infusion of labeled nicotine and cotinine, it has been determined that 70-80% of nicotine is converted to cotinine (Benowitz and Jacob 1994). About 4-7% of nicotine is excreted as nicotine N -oxide and 3-5% as nicotine glucuronide (Benowitz et al. 1994 Byrd et al. 1992). Cotinine is excreted unchanged in urine to a small degree (10-15% of the nicotine and metabolites in urine). The remainder is converted to metabolites, primarily fra i -3 -hydroxycotinine (33 0%), cotinine glucuronide (12-17%), and trans-3 -hydroxycotinine glucuronide (7-9%). 

The metabolism of cotinine is much slower than that of nicotine. Cotinine clearance averages about 45 ml min. Clearance of (3 7J, 5 5) -tra x-3 -hydroxycotinine is also quite slow - about 82 ml min . ... 

The 3 -hydroxycotinine/cotinine ratio (3HC/cotinine) in plasma and saliva has been evaluated as a non-invasive probe for CYP2A6 activity (Dempsey et al. 2004). The ratio was highly correlated with oral clearance of nicotine and the oral clearance and half-life of cotinine. Correlation coefficients of oral nicotine and cotinine clearances with plasma 3 -hydroxycotinine/cotinine ratios were 0.78 and 0.63, respectively, at 6 h after oral nicotine dosing. 

Renal clearance of cotinine is much less than the glomerular filtration rate (Benowitz et al. 2008b). Since cotinine is not appreciably protein bound, this indicates extensive tnbnlar reabsorption. Renal clearance of cotinine can be enhanced by np to 50% with extreme urinary acidification. Cotinine excretion is less influenced by urinary pH than nicotine becanse it is less basic and, therefore, is primarily in the unionized form within the physiological pH range. As is the case for nicotine, the rate of excretion of cotinine is influenced by urinary flow rate. Renal excretion of cotinine is a minor route of elimination, averaging about 12% of total clearance. In contrast, 100% of nicotine Ai -oxide and 63% of 3 -hydroxycotinine are excreted unchanged in the urine (Benowitz and Jacob 2001 Park et al. 1993). 

Byrd GD, Chang KM, Greene JM, deBethizy JD (1992) Evidence for urinary excretion of glu-curonide conjugates of nicotine, cotinine, and trans-3 -hydroxycotinine in smokers. Drug Metab Dispos 20(2) 192-197... 

Jacob P, 3rd, Benowitz NL (1991) Oxidative metabolism of nicotine in vivo. In F, Adlkofer, K, Thurau (eds) Effects of nicotine on biological systems, Birkhauser Verlag, Basel, pp 35 4 Jacob P, 3rd, Shulgin AT, Benowitz NL (1990) Synthesis of (3 R, 5 S)-trans-3 -hydroxycotinine, a major metabolite of nicotine. Metabolic formation of 3 -hydroxycotinine in humans is highly stereoselective, J Med Chem 33(7) 1888-1891... 

McKennis H, Jr., Turnbull LB, Bowman ER, Tamaki E (1963) The synthesis of hydroxycotinine and studies on its structure. J Org Chem 28 383-387 McNabb ME (1984) Chewing nicotine gum for 3 months what happens to plasma nicotine levels Can Med Assoc J 131(6) 589-592... 

Neurath GB (1994) Aspects of the oxidative metabolism of nicotine. Clin Investig 72(3) 190-195 Neurath GB, Dunger M, Orth D, Pein FG (1987) Trans-3 -hydroxycotinine as a main metabolite in urine of smokers. Int Arch Occup Environ Health 59(2) 199-201 Neurath GB, Orth D, Pein FG (1991) Detection of nomicotine in human urine after infusion of nicotine. In Adlkofer F, Thurau K (eds) Effects of nicotine on biological systems. Birkhauser Verlag, Basel, pp 45 9... 

Mouse CYP2A5 is a comparable isoform to human CYP2A6 (Raunio et al. 1988), because these isozymes are responsible for the majority of nicotine s C-oxidation (Raunio et al. 2008), cotinine s subsequent oxidation to 3 -hydroxycotinine (Sin and Tyndale 2007), and coumarin 7-hydroxylation (Kaipainen et al. 1984). Taken together, these findings suggest that mice may be a cost-effective animal model of human CYP2A6-mediated nicotine C-oxidation. 

Yamanaka H, Nakajima M, Katoh M, Kanoh A, Tamura O, Ishibashi H, Yokoi T (2005a) Trans-3 -hydroxycotinine O- and N-glucuronidations in human liver microsomes. Drug Metab Dispos 33 23-30... 

Among the alkaloids are some well-known (and dangerous) compounds. Nicotine is an agent in tobacco that has been described as one of the most toxic of all poisons and (it) acts with great rapidity. 13 In 1988, the U.S. Surgeon General declared nicotine to be an addictive substance. Nicotine is metabolized to cotinine and iran.v-3 -hydroxycotinine,... 

The major human urinary metabolites of nicotine are cotinine, nicotine A -oxide, and fra s-3 -hydroxycotinine (113). CYP2A6 appears to be the major enzyme responsible for formation of an iminium ion that is the first step in the C-5 oxidation of nicotine to cotinine and also the subsequent... 

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