Known and novel sources of variability in the nicotine metabolite ratio in a large sample of treatment-seeking smokers

Abstract

Background: The ratio of 3'hydroxycotinine to cotinine, or nicotine metabolite ratio (NMR), is strongly associated with CYP2A6 genotype, CYP2A6-mediated nicotine and cotinine metabolism, and nicotine clearance. Higher NMR (faster nicotine clearance) is associated retrospectively with heavier smoking and lower cessation rates.

Methods: NMR as a predictive biomarker of cessation outcomes is being investigated (NCT01314001). In addition to strong CYP2A6 genetic influences on NMR, demographic and hormonal factors alter NMR. Here, we analyzed, for the first time together, these sources of variation on NMR in smokers screened for this clinical trial (N = 1,672).

Results: Participants (mean age = 45.9) were 65.1% Caucasian, 34.9% African American, and 54.8% male. Mean NMR (SD) was higher in Caucasians versus African Americans [0.41 (0.20) vs. 0.33 (0.21); P < 0.001], and in females versus males [0.41 (0.22) vs. 0.37 (0.20); P < 0.001]. Among females, birth control pill use (N = 17) and hormone replacement therapy (N = 14) were associated with 19.5% (P = 0.09) and 29.3% (P = 0.06) higher mean NMR, respectively, albeit nonsignificantly. BMI was negatively associated with NMR (Rho = -0.14; P < 0.001), whereas alcohol use (Rho = 0.11; P < 0.001) and cigarette consumption (Rho = 0.12; P < 0.001) were positively associated with NMR. NMR was 16% lower in mentholated cigarette users (P < 0.001). When analyzed together in a linear regression model, these predictors (each ≤2%) accounted for <8% of total NMR variation.

Conclusions: Although these factors significantly affected NMR, they contributed little (together <8%; each ≤2%) to total NMR variation.

Impact: Thus, when using NMR, for example, to prospectively guide smoking cessation therapy, these sources of variation are unlikely to cause NMR misclassification.

Figure 1

Variation in the nicotine metabolite ratio (NMR) according to ethnicity and gender in Caucasian and African American adult smokers NMR is shown as a function of ethnicity (A) and gender (B) in the total group (Mann-Whitney U tests).

Figure 2

Association between exogenous estrogen-containing therapy and NMR among females NMR is shown as a function of estrogen-containing birth control (BC) pill use in all females and Caucasian females (A) and as a function of estrogen-containing hormone replacement therapy (HRT) use in all females and Caucasian females (B) (Mann-Whitney U tests).

Figure 3

Associations for NMR with BMI, alcohol consumption, cigarette use, and menthol Correlations between BMI and NMR (A) and alcohol use (# standard drinks/week) and NMR (B) are shown in the total group. The association between mentholated cigarette use and NMR in the intent-to-treat group (where it was available) is shown in (C), while the association between NMR, as a median split, and CPD is depicted in the total group in (D) (Mann-Whitney U tests).