Metabolism of NNK in Japanese Americans

Study Overview
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Brief Summary
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The risk of lung cancer varies by individual and by ethnic/racial group. In this study the investigators will explore how individual differences in the metabolism of a tobacco-specific lung carcinogen may contribute to the variable risk of lung cancer between ethnic/racial groups. In this 10 day clinical trial, Japanese Americans will smoke a cigarette containing deuterium-labeled 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific lung carcinogen. The study cigarette will be smoked for 7 days. This will allow for NNK metabolic profiling and determining the effect of CYP2A6 genotype on the level of NNK α-hydroxylation in Japanese Americans smokers using [pyridine- D4]-NNK containing cigarettes.

Detailed Description
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Eligible subjects will provide a baseline 24 hour urine sample. Study cigarettes spiked with labeled NNK will be provided to the subjects to smoke over a 7 day period. During this time, 24 hour urine samples will be collected over days 5, 6 and 7 on study cigarettes. Blood will be drawn on days 6 and 7 on study cigarettes. Samples will be analyzed for NNK metabolism.

Official Title
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STUDY 2: CLINICAL PROTOCOL Metabolism of NNK Among Japanese Americans

Conditions
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Smoking

Intervention / Treatment
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* Combination Product: Modified Natural American Spirit-Tan or Green cigarettes injected with labeled NNK


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Japanese American - one, but preferably 2 biological parents of Japanese descent 21 years or older Daily smoker Eligible urinary ratios of total 3-hydroxycotinine to cotinine (3HC/COT): Little or no-CYP2A6 activity defined as a 3-hydroxycotinine:cotinine ratio of <0.6 or Relatively high CYP2A6 activity defined as a 3-hydroxycotinine:cotinine ratio of >3.0. Stable and good physical and mental health Provided written informed consent to participate in the study Exclusion Criteria: Unwilling to avoid other nicotine containing products during the study and no use of any nicotine-containing products except cigarettes for 1 week prior to their study visits Currently taking any medications that affect relevant metabolic enzymes Experiencing medical conditions that might affect biomarkers of exposure and effect Pregnant or nursing or planning on becoming pregnant during the study Unable to read and understand English

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Smokers with very low or no CYP2A6 activity<br>Japanese American smokers (daily > 5 cigarettes) with little or no CYP2A6 activity (CYP2A6 activity defined as a ratio of trans-3-hydroxycotinine:cotinine ratio of <0.6). | Combination Product: Modified Natural American Spirit-Tan or Green cigarettes injected with labeled NNK<br>* American Spirit cigarettes will be modified by adding 0.300 μg [pyridine-D4]NNK to each cigarette so that the amount of total (deuterated plus unlabeled) NNK in these cigarettes is below 0.700 μg/g tobacco.<br>|
| Smokers with high CYP2A6 activity<br>Japanese American smokers (daily > 5 cigarettes) with high CYP2A6 activity (CYP2A6 activity defined as a ratio of trans-3-hydroxycotinine:cotinine ratio of > 3.0) | Combination Product: Modified Natural American Spirit-Tan or Green cigarettes injected with labeled NNK<br>* American Spirit cigarettes will be modified by adding 0.300 μg [pyridine-D4]NNK to each cigarette so that the amount of total (deuterated plus unlabeled) NNK in these cigarettes is below 0.700 μg/g tobacco.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of CYP2A6 genotype on the level of NNK α-hydroxylation administered [pyridine-D4]-D4 NNK. | Comparison between the means of the two groups (null versus average CYP2A6) in smokers receiving [Pyridine D4]-NNK. The extent of NNK α-hydroxylation in the two groups will be described by a ratio of NNK metabolites, D4- α-hydroxymethyl NNK Gluc (or other products of α-hydroxylation) to D4-NNAL. The ratio is used as a measure of the pathway as a percent of dose. | 7 days | 
| NNK metabolic profiles | Characterization of metabolites variation and covariation of NNK, NNAL-N-oxide, NNAL-glucuronides, α-hydroxy glucuronides and other NNK metabolites identified in smokers receiving [Pyridine D4]-NNK | 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CYP2A6, Nicotine Metabolite Ratio, NNAL, NNK α-hydroxylation