Pharmacokinetic Evaluation of a Cinnamon Product on <scp>CYP2A6</scp> Substrate Drugs: Application of a Novel Tool Involving the Nicotine Metabolite Ratio

Cinnamon (Cinnamomum spp.) is used as a culinary spice and dietary supplement. A major constituent, cinnamaldehyde, was previously shown to inactivate cytochrome P450 (CYP) 2A6 in vitro. A mechanistic static model predicted an ~5-fold increase in the AUC of the CYP2A6 substrates nicotine and letrozole. Accordingly, the effects of a well-characterized cinnamon (Cinnamomum verum) product on the pharmacokinetics of nicotine and letrozole were evaluated in 16 healthy, non-nicotine using adults. They were administered a single dose of nicotine gum (2 mg) or letrozole tablet (2.5 mg) (baseline). After a sufficient washout (2-14 days), they self-administered C. verum (2 g thrice daily) for 5 consecutive days. On Day 6, they were administered C. verum with nicotine or letrozole, followed by two more doses of C. verum (cinnamon exposure). Plasma was collected from 0 to 12 (nicotine) or 0-240 (letrozole) hours. The geometric mean plasma concentration vs. time profile for both drugs was nearly superimposable in the presence vs. absence of C. verum. The geometric mean ratio (GMR) [90% confidence interval] of the AUC of nicotine and letrozole in the presence to absence of cinnamon was 0.98 [0.96-1.12] and 1.11 [0.98-1.24], respectively (P > 0.16), indicating no interactions. Application of the "slope approach" involving the 3-hydroxycotinine-to-cotinine ratio provided potential new mechanistic insight into CYP2A6 inhibition. The general lack of effect of a typical dosage of C. verum on the pharmacokinetics of nicotine and letrozole suggests that C. verum may be safe to consume with both drugs, as well as other CYP2A6 substrates.