# Natural Compounds in the Battle against Microorganisms--Linalool
## 2 Metabolism of Linalool  
Although linalool has several beneficial effects on the human body, little data are available on its metabolism in humans. After inhalation for 45 min (10% _v/v_ (3_R_)-(-)-linalool in propylene glycol solution), the compound appeared in the blood after 25 min and lasted for about 40-45 min [43]. On the other hand, when (3_R_)-(--)-linalool in peanut oil was applied to the skin, terpene alcohol was detected in the blood about 30 min after the massage. Interestingly, when applied to the skin, males showed better absorption than females. The longer time of penetration into the blood after application to the skin may be due to its accumulation in the subcutaneous fatty tissue [44]. Linalool readily penetrates the stratum corneum and the rate of decline is estimated at 10-20% per hour after cessation of exposure [45]. In the case of massage using lavender oil and peanut oil, linalool appeared in the bloodstream within 5 min of the end of the massage (total massage time was 10 min), and the maximum concentration was observed after 19 min [43]. When administered orally, linalool appeared in the blood of the subjects approximately 10-15 min after consuming 200 \(\upmu\)L of lavender oil, with the maximum concentration observed after 30 min [46]. Linalool biotransformations were performed using human recombinant CYP2D6 and CYP2C19. Both CYP isoforms are present in human skin. The major product was _cis_- and _trans_-8-hydroxylinalool. Allylic hydroxylation was catalyzed by both enzymes, while enzymatic epoxidation of linalool to yield 6,7-epoxy-linalool was catalyzed only by CYP2D6. Trace formation of (_R_/S)-furanoid-linalool oxide and (_R_/S)-pyranolol-linalool oxide, which are products of intramolecular rearrangement due to the attack of the hydroxyl group on the epoxy bond, has also been observed. It is worth noting that the enzymatic affinity of CYP2D6 for the enzymatic epoxidation of the double bond was approximately 3-10 times lower than the enzymatic affinity for the hydroxylation reaction. The catalytic yields of cyclic ether formation were approximately in the same range but approximately 3000-4000 times lower than that of the hydroxylation reaction [47] (Scheme 1). In animals, the first attempts to study the metabolism of linalool in vivo were made at the beginning of the 20 th century, when in 1904, [PERSON] conducted research on rabbits. He showed that linalool is excreted as glucuronide [48]. In 1974, [PERSON] et al. [49] investigated the distribution of [14C] linalool in rats and observed that after a single oral dose, about 58% of the administered linalool was excreted in the urine, and 25% as 14 CO2 in the expired air and 16% in the faeces after 72 h. About 10% of the administered dose was excreted as [14C] urea in the urine. Additionally, linalool derivatives such as dihydro- and tetrahydromalool (free and conjugated) have also been detected in significant amounts in urine. It was observed that when administered to rats, linalool induced hepatic microsomal cytochrome P-450 and UDP-glucuronyl transferase [50]. Further studies have shown that linalool is first converted by cytochrome P-450 (CYP) isoenzymes to dihydrolinalool and tetrahydromalool and to 8-hydroxylinalool, which is further oxidized to 8-carboxylinalool (Scheme 2). The resulting compound is then converted into a glucuronide conjugate and, as such, form excreted from the body [51]. It is worth mentioning that pulmonary microsomes obtained from rats pre-treated with \(b\)-naphthoflavone catalyzed the formation of 8-hydroxylinalool from linalool [52]. Further studies showed that in rats, (3_R_)-(\(-\))-linalool induces CYP2A and does not affect 2B, 2C6, 2C11 and 3A [53]. The CYP2A family in rats includes CYP2A1 and CYP2A2 in liver tissue and CYP2A3 in the lung.