The administration of deuterated nicotine allows for direct measurement of the conversion of nicotine to its primary metabolites. Two metabolism metrics were initially calculated, the ratio of D2-cotinine: D2-nicotine and the ratio D2-cotinine: (D2-nicotine + D2-cotinine). The ratio of substrate to metabolite is conventionally normalized by log transformation for analysis. The latter metric has been previously suggested as more stable than the metabolite/substrate ratio [33, 34]and was pursued here for multiple reasons. Firstly, it does not require log-transformation for analysis. The distribution of D2-cotinine: D2-nicotine before log-transformation is skewed toward faster metabolism (Supplemental Fig.1), even after correcting for genotype (Supplemental Table 2 and Supplemental Fig.2). On the other hand, the distribution of D2-cotinine: (D2-nicotine + D2-cotinine) is skewed toward slow metabolism, typical of a phenotype influenced by a ‘gene of large effect’ (Tucker et al. 1998), consistent with the known dominance of one enzyme, CYP2A6, over nicotine’s conversion to cotinine. However, after correcting for CYP2A6 genotype, D2-cotinine: (D2-nicotine + D2-cotinine) is normally distributed for common diplotypes (Supplemental Table 2 and Supplemental Fig.2), indicating that the skew in this metric results
