UCSF

Background

Variation in CYP2A6 activity influences tobacco smoking behaviors and smoking-related health outcomes. Plasma Nicotine Metabolite Ratio (NMR) is a robust phenotypic biomarker of CYP2A6 activity and nicotine clearance. In urine, the NMR has been calculated as a ratio of free trans-3'-hydroxycotinine to free cotinine (NMR_F/F), total trans-3'-hydroxycotinine to free cotinine (NMR_T/F), or total trans-3'-hydroxycotinine to total cotinine (NMR_T/T). We evaluated these three urinary NMR versions relative to plasma NMR and nicotine clearance and elucidated mechanisms of discrepancies among them.

Methods

Baseline plasma and urine biomarker data were available from two smoking cessation clinical trials and one nicotine pharmacokinetic study (total N = 768). NMRs were compared using Pearson correlations, linear regressions and ANOVA analyses. UGT2B10 and UGT2B17 were genotyped.

Results

Urinary NMR_T/F was the most highly related to plasma NMR (R² = 0.70, P <2.2e-16) followed by NMR_F/F (R² = 0.68, P <2.2e-16), while NMR_T/T was less strongly related (R² = 0.60, P <2.2e-16); consistent across study, ethnicity, sex, heaviness of smoking, and analyte analysis. Controlling for cotinine glucuronidation, as a phenotype or UGT2B10 genotype, corrected the NMR_T/T discordance with plasma NMR (P_anova<0.001). Similar findings were obtained for relationships of nicotine clearance with plasma NMR > urinary NMR_T/F > NMR_F/F > NMR_T/T (R² = 0.41 > 0.37 > 0.35 > 0.25 respectively).

Conclusion

Urinary NMR_T/F followed by NMR_F/F are the best urinary alternatives to plasma NMR or nicotine clearance. NMR_T/T has the least utility as it is influenced substantially by variation in cotinine glucuronidation.

Impact

This work highlighted the variation in urinary NMRs, and identified mechanisms for disparities among them, which facilitates their use in predicting smoking-related outcomes.