Linalool, Linalyl Acetate, and Lavender Essential Oil: Evaluation of Metabolism and Drug Interactions Using Canine Liver Microsomes and Recombinant Enzymes

1. Pharmacokinetic interactions between natural extracts and hepatic cytochrome P450 (CYP) enzymes are a concern in veterinary medicine. Lavender essential oil (LEO), containing linalool (LIN) and linalyl acetate (LINAc), may be coadministered with conventional medicines for treatment of canine anxiety.2. This study examined the canine metabolism of LIN and LINAc by substrate depletion using pooled dog liver microsomes (pDLMs) and recombinant canine CYP enzymes (rCYPs). Inhibitory effects of LIN, LINAc, and LEO on CYP isoform-selective probe drug reactions were also evaluated.3. LINAc was hydrolyzed to LIN by a heat-sensitive esterase activity in pDLMs. LIN depletion by pDLMs was NADPH-dependent, saturable with a Michaelis-Menten constant of 52 ± 11 µM, and induced by over 5-fold in liver microsomes from phenobarbital-treated dogs. Recombinant CYP2B11 showed the highest LIN depletion activity, followed by CYP2C21, while other CYPs tested did not show measurable substrate depletion. Inhibition experiments showed that LIN, LINAc, and LEO inhibited CYP2B11-mediated metabolism but not metabolism by CYP2C21, CYP2D15, or CYP3A12. IC₅₀ values for LIN, LINAc, and LEO were 7.1, 2.7, and 2.5 µM for tramadol N-demethylation, and 13.9, 8.0, and 8.6 µM for methadone-N-demethylation, respectively. Interestingly, none of the terpenes were shown to directly inhibit recombinant CYP2B11 activity, suggesting that they exerted indirect inhibition via metabolites generated by other CYPs in pDLMs.4. These findings highlight CYP2B11 and CYP2C21 as key enzymes in LIN and LINAc metabolism and underscore the potential for herb-drug interactions when treating dogs with lavender essential oil.