Pharmacokinetics and Tissue Distribution of the Sesquiterpene α-Humulene in Mice

Abstract

A quantitative study was undertaken to assess the plasma and tissue levels, tissue distribution and skin (ear) absorption of the sesquiterpene alpha-humulene, the main active constituent isolated from the plant Cordia verbenacea (Boraginaceae ), after oral, intravenous and topical administration in mice. The alpha-humulene levels were quantified by GC-MS analysis. The peak alpha-humulene concentration was achieved 15 min following its oral administration (150 mg/kg). Then, the alpha-humulene plasma concentration gradually decreased and it was almost undetectable at 2 hours after intravenous administration and 12 hours after oral administration. When the oil of C. verbenacea was given orally (1 g/kg), the peak alpha-humulene plasma concentration was observed after 30 min, being detectable only up to 2 h. The oral bioavailability of alpha-humulene was found to be 18 %. The half-lives of alpha-humulene were very short, 16.8 min after oral administration and 1.8 min after intravenous administration. However, the elimination half-lives were longer, 118.2 min and 55 min, for oral and intravenous routes, respectively. We also assessed the amount of alpha-humulene in some selected tissues at 0.5 and at 4 h after oral administration. We found a high amount of the compound in the liver, followed by the kidneys, heart, lungs, spleen and brain, 0.5 h after oral administration. Notably, the yield of alpha-humulene decreased significantly in all analyzed tissues, especially in the liver, 4 h after oral administration. Of note, 30 minutes after topical administration of Acheflan formulations (cream and aerosol) containing 0.5 % of C. verbenacea essential oil, a schedule of treatment that produces marked and similar topical anti-inflammatory activity, the amount of alpha-humulene absorbed in the ear was very similar (about 2 microg/ear). It is concluded that alpha-humulene exhibited a rapid onset and relatively good absorption following oral and topical administration. Taken together, these findings further contribute to an explanation of the topical and systemic anti-inflammatory and antinociceptive properties previously reported for the essential oil and for alpha-humulene obtained from Cordia verbenacea, they also provide support for the clinical studies conducted with the phytomedicine Acheflan.

Intestinal Permeability of Sesquiterpenes in the Caco-2 Cell Monolayer Model

“…These results suggest that passive diffusion is the main transport mechanism of all the sesquiterpenes tested across the Caco-2 cell monolayer and predict that they are the well-absorbed compounds in human intestine. Similar results were also found for some active sesquiterpenes, such as onitin [24], α-humulene [25], artemisinin [26] and parthenolide [27], which were all well-transported compounds by passive diffusion. The secretory permeability (P app BL→AP , 5.754 ± 0.817 × 10 −5 cm/s) of ICL was significantly higher than its absorptive permeability (P app AP→BL , 2.439 ± 0.505 × 10 −5 cm/s) and the ratio of P app AP→BL to P app BL→AP of ICL was 0.424 (l " Table 2), suggesting greater permeability in the BL to AP direction and the possible involvement of efflux transport [18].…”

Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain: An Update on Current Evidence and Cannabis Science

“…It is found in herbs and spices such as hops, clove, basil, sage, ginger, spearmint, and ginseng as well as some fruits and vegetables. It has strong anti‐inflammatory properties comparable to dexamethasone systemically, topically, and in allergic airway inflammation, as well as anti‐nociceptive and analgesic properties . It has anti‐cancer activity, is anti‐bacterial including activity against Staphylococcus aureus , and insecticidal/larvicidal effects have been documented.…”

Sesquiterpenoids Lactones: Benefits to Plants and People

“…Sharp had an LC 50 of 45.31 μg/mL in a brine shrimp test using three tumor cell lines. Chaves [61] determined that bioavailability of the sesquiterpene α-humulene in mice was as high as 18% when applied orally, and remained detectable up to 12 h after administration, and also showed that the compound was able to cross the blood-brain barrier which would explain the antinociceptive effects attributed to Cordia verbenacea DC.…”