CYP2A6 genotype and the metabolism and disposition kinetics of nicotine

Benowitz, Neal L.; Swan, Gary E.; Jacob, Peyton; Lessov‐Schlaggar, Christina N.; Tyndale, Rachel F.

doi:10.1016/j.clpt.2006.08.011

Cited by 196 publications

(225 citation statements)

References 28 publications

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“…This change was attributed to increased activity of CYP 2A6, which had greater effects on the clearance of cotinine than of nicotine. Similarly, gender and use of oral contraceptives, both thought to effect CYP2A6 activity, had greater impact on cotinine clearance than on the fractional clearance of nicotine to cotinine (Benowitz et al, 2006b).…”

Section: Rapid Nicotine Clearance Associated With Greater Reward M Somentioning

confidence: 99%

Rapid Nicotine Clearance is Associated with Greater Reward and Heart Rate Increases from Intravenous Nicotine

Sofuoglu

Herman

Nadim

et al. 2012

Neuropsychopharmacol

102

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The ratio of nicotine metabolites (trans-3 0 -hydroxycotinine (3HC) to cotinine) correlates with nicotine clearance. In previous studies, high nicotine metabolite ratio (NMR) predicted poor outcomes for smoking cessation treatment with nicotine patch. The underlying mechanisms that associate NMR with treatment outcomes have not been fully elucidated. A total of 100 smokers were divided into quartiles based on their baseline plasma NMR. Following overnight abstinence, smokers received saline followed by escalating intravenous doses of nicotine (0.5 and 1.0 mg/70 kg) given 30 min apart. The effects of nicotine on subjective, plasma cortisol, heart rate, and systolic and diastolic blood pressure measures were obtained. Smokers in the first NMR quartile (slower metabolizers) had lower Fagerstrom Test for Nicotine Dependence (FTND) scores, suggesting lower levels of dependence. In contrast, smokers in the fourth NMR quartile (faster metabolizers) reported greater craving for cigarettes following overnight abstinence from smoking and reported greater ratings of nicotine-induced good drug effects, drug liking, and wanting more drug. Higher NMR was also associated with greater heart rate increases in response to nicotine. These results suggest that enhanced nicotine reward and cigarette craving may contribute to the poor treatment response in smokers with high NMR. These findings warrant further investigation, especially in treatment-seeking smokers undergoing cessation treatment.

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Section: Rapid Nicotine Clearance Associated With Greater Reward M Somentioning

confidence: 99%

Rapid Nicotine Clearance is Associated with Greater Reward and Heart Rate Increases from Intravenous Nicotine

Sofuoglu

Herman

Nadim

et al. 2012

Neuropsychopharmacol

102

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“…The 3HC/COT is a validated phenotypic measure of CYP2A6 activity and rates of nicotine metabolism [23], with previous studies finding a significant association between the ratio and CYP2A6 genotype [38][39][40]. Because the 3HC/COT ratio did not differ significantly from CYP2A6*1/*1 individuals in this population of Black-African descent, the wildtype group (*1/*1) included individuals with the CYP2A6*1B allele.…”

Section: Cyp2a6*23 Decreased the Rate Of Nicotine Metabolism In Vivo mentioning

confidence: 99%

A novel CYP2A6 allele, CYP2A6*23, impairs enzyme function in vitro and in vivo and decreases smoking in a population of Black-African descent

Mwenifumbo

Zhao

et al. 2008

Pharmacogenetics and Genomics

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Objectives-CYP2A6 is the main enzyme involved in nicotine metabolism in humans. We have identified a novel allele, CYP2A6*23 (2161C>T, R203C), in individuals of Black-African descent and investigated its impact on enzyme activity and association with smoking status.Methods-Wildtype and variant enzymes containing amino acid changes R203C (CYP2A6*23), R203S (CYP2A6*16) and V365M (CYP2A6*17) were expressed in Escherichia coli. The effect of CYP2A6*23 in vivo was examined in individuals of Black-African descent given 4 mg oral nicotine.Results-CYP2A6*23 occurred at an allele frequency of 2.0% in individuals of Black-African descent (N = 560 alleles, 95% confidence interval 0.8%-3.1%) and was not detected in Caucasians (N = 334 alleles), Chinese (N = 288 alleles) or Japanese (N = 104 alleles). In vitro, CYP2A6.23 had greatly reduced activity towards nicotine C-oxidation similar to CYP2A6.17, as well as reduced coumarin 7-hydroxylation. Conversely, CYP2A6.16 did not differ in activity compared to the wildtype enzyme. The trans-3′-hydroxycotinine to cotinine ratio, a phenotypic measure of CYP2A6 activity in vivo, was lower in CYP2A6*1/*23 and CYP2A6*23/*23 individuals(mean adjusted ratio of 0.60, n = 5) compared to CYP2A6*1/*1 individuals (mean adjusted ratio of 1.21, n = 150) (p < 0.04). CYP2A6*23 trended towards a higher allele frequency in nonsmokers (3.1%, N = 9/286 alleles) compared to smokers (0.7%, N = 2/274 alleles) (p = 0.06).Conclusions-These results suggest the novel CYP2A6*23 allele impairs enzyme function in vitro and in vivo and trends toward an association with lower risk of smoking.

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“…determination of serum cotinine concentrations [13] has been applied to the analysis of d 2 -cotinine [14][15][16]. Two of these studies also quantified urine concentrations of d 2 -nicotine by LC/MS/MS [15;16], but GC/MS analysis was used to quantify plasma d 2 -nicotine, suggesting that the LC/MS/MS method used was not sufficiently sensitive for the analysis of the lower d 2 -nicotine concentrations in plasma.…”

Section: Introductionmentioning

confidence: 99%

Analysis of [3′,3′-d2]-nicotine and [3′,3′-d2]-cotinine by capillary liquid chromatography–electrospray tandem mass spectrometry

Murphy

Villalta

et al. 2007

Journal of Chromatography B

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A selective and sensitive LC/MS/MS assay was developed for the quantification of d 2 -nicotine and d 2 -cotinine in plasma of current and past smokers administered d 2 -nicotine. After solid phase extraction and liquid liquid extraction, HPLC separation was achieved on a capillary hydrophilic interaction chromatography phase column. The analytes were monitored by tandem mass spectrometry with electrospray positive ionization. Linear calibration curves were generated for d 2 -nicotine (0.03 to 6.0 ng/ml plasma) and d 2 -cotinine (0.15 to 25 ng/ml plasma). The lower limits of quantitation were 0.15 ng/ml and 0.25 ng/ml for d 2 -nicotine and d 2 -cotinine, respectively. The coefficient of variation was 3.7% for d 2 -nicotine and 2.5% for d 2 -cotinine. The method was applied to two ongoing studies of d 2 -nicotine metabolism in prior and current smokers. Preliminary analysis of a subset of subjects from these studies detected a significantly lower rate of nicotine conversion to cotinine by past smokers compared to current smokers.

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CYP2A6 genotype and the metabolism and disposition kinetics of nicotine

Abstract: We provide novel pharmacokinetic and metabolic data on nicotine after systemic dosing in relation to common CYP2A6 genotypes. Our data will enhance the interpretation of CYP2A6 genotypic data as used in association studies of smoking behavior and its health consequences.

Cited by 196 publications

References 28 publications

Rapid Nicotine Clearance is Associated with Greater Reward and Heart Rate Increases from Intravenous Nicotine

Rapid Nicotine Clearance is Associated with Greater Reward and Heart Rate Increases from Intravenous Nicotine

A novel CYP2A6 allele, CYP2A6*23, impairs enzyme function in vitro and in vivo and decreases smoking in a population of Black-African descent

Analysis of [3′,3′-d2]-nicotine and [3′,3′-d2]-cotinine by capillary liquid chromatography–electrospray tandem mass spectrometry

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