Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity

• Published in: Clinical pharmacology and therapeutics Vol. 76; no. 1; p. 64
• Main Authors: Dempsey, Delia, Tutka, Piotr, Jacob, 3rd, Peyton, Allen, Faith, Schoedel, Kerri, Tyndale, Rachel F, Benowitz, Neal L
• Format: Journal Article
• Language: English
• Published: United States 01.07.2004
• Subjects: Adult; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Cotinine - analogs & derivatives; Cotinine - blood; Cytochrome P-450 CYP2A6; Female; Humans; Male; Middle Aged; Mixed Function Oxygenases - genetics; Mixed Function Oxygenases - metabolism; Nicotine - metabolism; Saliva - metabolism
• ISSN: 0009-9236
• DOI: 10.1016/j.clpt.2004.02.011

Nicotine and a variety of other drugs and toxins are metabolized by cytochrome P450 (CYP) 2A6. Our objective was to evaluate the use of oral nicotine with measurement of the trans-3'-hydroxycotinine (3HC)/cotinine (COT) metabolite ratio as a noninvasive probe of CYP2A6 activity. Sixty-two healthy volunteers received an oral solution of deuterium-labeled nicotine (2 mg) and its metabolite cotinine (10 mg). Plasma nicotine and plasma and saliva cotinine and 3HC concentrations were measured over time. The 3HC/COT ratio derived from deuterium-labeled cotinine, measured in either plasma (2-8 hours after administration) or saliva (at 6 hours), was strongly correlated with the oral clearance of nicotine (r = 0.76-0.83, depending on the time of measurement). The 6-hour 3HC/COT ratio from nicotine derived from tobacco in 14 smokers was highly correlated with the ratio derived from deuterium-labeled nicotine (r = 0.88) and was also highly correlated with the oral clearance of nicotine (r = 0.90). Two subjects homozygous for inactive CYP2A6 alleles produced no 3HC, confirming the specificity of the metabolite ratio. The 3HC/COT ratio was also highly correlated with the clearance and half-life of cotinine, consistent with the fact that cotinine is also primarily metabolized by CYP2A6. The 3HC/COT ratio derived from nicotine either administered as a probe drug or from tobacco use, measured in either plasma or saliva, is highly correlated with the oral clearance of nicotine. The ratio appears to be a useful noninvasive marker of the rate of nicotine metabolism (which is important in studying nicotine addiction and smoking behavior), as well as a general marker of CYP2A6 activity (which is important in studying drug and toxin metabolism).