Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity*1

Dempsey, Delia; Tutka, Piotr; Jacob, Peyton; Allen, Faith; Schoedel, Kerri A.; Tyndale, Rachel F.; Benowitz, Neal L.

doi:10.1016/j.clpt.2004.02.011

Cited by 388 publications

(477 citation statements)

References 24 publications

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“…Analysis may be carried out on as little as 20 µl of plasma and the limits of quantitation for d 2 -cotinine and d 2 -nicotine were 0.25 ng/ml and 0.15 ng/ml, respectively. These limits are similar to what has been reported previously for the analysis of d 2 -cotinine in plasma by APCI LC/MS/MS [14]. The method is being applied to on-going studies of nicotine metabolism in smokers and non-smokers administered d 2 -nicotine.…”

Section: Discussionsupporting

confidence: 83%

“…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%

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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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Section: Discussionsupporting

confidence: 83%

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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“…173 CYP2A6 is located on chromosome 19 (19q13.2) and a nearby region was associated with smoking frequency (X1 cigarette per day) in a genome-wide linkage scan. 39 Large interindividual and interethnic variations in CYP2A6 activity have been reported; [170][171][172][174][175][176][177] this variability is mainly attributed to the large genetic variations in CYP2A6. 178,179 A brief summary of how genetic variations in CYP2A6 affect smoking behaviors will be provided here as a detailed review was recently published.…”

Section: Other Likely Candidates Involved In Neurotransmitter Systemsmentioning

confidence: 99%

Overview of the pharmacogenomics of cigarette smoking

Tyndale

2007

Pharmacogenomics J

102

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Cigarette smoking increases the risk of numerous health problems, including cancer, cardiovascular and pulmonary disorders, making smoking the leading cause of preventable death in the world. Nicotine is primarily responsible for the highly addictive properties of cigarettes. Although the majority of smokers express a desire to quit, few are successful in doing so. Twin and family studies have indicated substantial genetic contributions to smoking behaviors. One major research focus has been to elucidate the specific genes involved; this has been accomplished primarily through genome-wide linkage analyses and candidate gene association studies. Much attention has focused on genes involved in the neurotransmitter pathways for the brain reward system and genes altering nicotine metabolism. This paper reviews the current state of knowledge for genetic factors implicated in smoking behaviors, and examines how genetic variations may affect therapeutic outcomes for drugs used to assist smoking cessation.

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“…A first proof was provided by Dempsey et al, who administered deuterium labeled nicotine and cotinine to 62 healthy volunteers. Resulting trans 3'-OH-cotinine/cotinine ratios in oral fluid 6 h post-intake were highly correlated with several indices of CYP2A6 activity, including 6 h ratios in plasma and oral clearance of both nicotine and cotinine [111]. CYP2A6 phenotyping based on trans 3'-OH-cotinine/cotinine ratios originating from nicotine in tobacco smoke was examined by St. Helen et al Regression analysis revealed high correlations between ratios in oral fluid and both whole blood and plasma of smokers and nonsmokers exposed to tobacco smoke.…”

Section: Oral Fluidmentioning

confidence: 93%

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

2015

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Interindividual variability in the expression and function of drug metabolizing cytochrome P (CYP) 450 enzymes, determined by a combination of genetic, non-genetic and environmental parameters, is a major source of variable drug response. Phenotyping by administration of a selective enzyme substrate, followed by the determination of a specific phenotyping metric, is an appropriate approach to assess the in vivo activity of CYP450 enzymes, as it takes into account all influencing factors. A phenotyping protocol should be as simple and convenient as possible. Typically, phenotyping metrics are determined in traditional matrices, such as blood, plasma or urine. Several sampling strategies have been proposed as an alternative for these traditional sampling techniques.In this review, we provide a comprehensive overview of available methods using dried blood spots, hair, oral fluid, exhaled breath and sweat for in vivo CYP450 phenotyping. We discuss the relation between phenotyping metrics measured in these samples and those in conventional matrices, along with the advantages and limitations of the alternative sampling techniques. Reliable phenotyping procedures for several clinically relevant CYP450 enzymes, including CYP1A2, CYP2C19 and CYP2D6, are currently available for oral fluid, breath or dried blood spots, while additional studies are needed for other CYP450 isoforms, such as CYP3A4. The role of hair analysis for this purpose remains to be established. Being non-or minimally invasive, these sampling strategies provide convenient and patient-friendly alternatives for classical phenotyping procedures, which may contribute to the implementation of CYP450 phenotyping in clinical practice. 4 Key Points Phenotyping by administration of a selective probe drug, followed by determination of a specific phenotyping metric, allows to assess the in vivo enzyme activity of CYP450 enzymes, taking into account genetic, non-genetic and environmental influencing factors. In addition to classical sampling techniques, such as blood or urine collection, reliable phenotyping procedures for several clinically relevant CYP450 enzymes are currently available for oral fluid, breath and dried blood spots.

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Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity*1

Cited by 388 publications

References 24 publications

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

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

Overview of the pharmacogenomics of cigarette smoking

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

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