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 α-humulene, the main active constituent isolated from the plant Cordia verbenacea (Boraginaceae), after oral, intravenous and topical administration in mice. The α-humulene levels were quantified by GC-MS analysis. The peak α-humulene concentration was achieved 15 min following its oral administration (150 mg/kg). Then, the α-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 α-humulene plasma concentration was observed after 30 min, being detectable only up to 2 h. The oral bioavailability of α-humulene was found to be 18 %. The half-lives of α-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 α-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 α-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 α-humulene absorbed in the ear was very similar (about 2 μg/ear). It is concluded that α-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 α-humulene obtained from Cordia verbenacea, they also provide support for the clinical studies conducted with the phytomedicine Acheflan®.

Abbreviations

AUC:area under the plasma level/time curve

C_max:maximum peak concentration

GC-MS:gas chromatography/mass spectrometry

T_max:time to achieve C_max

T_œ:half-life

T_{œ a}:half-life of absorption

T_{œ b}:half-life of elimination

Cordia verbenacea - Boraginaceae - α-humulene - Acheflan® - pharmacokinetics - bioavailability - skin absorption - tissue distribution

References

• 1 Calixto J B. Twenty-five years of research on medicinal plants in Latin America: a personal view.  J Ethnopharmacol. 2005;  100 131-4
• 2 de Carvalho P M, Rodrigues R FO, Sawaya A CHF, Marques M OM, Shimizu M T. Chemical composition and antimicrobial activity of the essential oil of Cordia verbenacea DC.  J Ethnopharmacol. 2004;  95 297-301
• 3 Akisue M K, Oliveira F, Moraes M S, Akisue G, Mancini B. Caracterização farmacognóstica da droga e da tintura se Cordia verbenacea D.C. – Boraginacea.  Rev Bras Cienc Farm. 1983;  5 69-82
• 4 Sertie J A, Woisky R G, Wiezel G, Rodrigues M. Pharmacological assay of Cordia verbenacea V: oral and topical anti-inflammatory activity, analgesic effect and fetus toxicity of a crude leaf extract.  Phytomedicine. 2005;  12 338-44
• 5 Fernandes E S, Passos G F, Medeiros R, da Cunha F M, Ferreira J, Campos M M. et al . Anti-inflammatory effects of compounds alpha-humulene and (–)-trans-caryophyllene isolated from the essential oil of Cordia verbenacea. .  Eur J Pharmacol. 2007;  569 228-36
• 6 Medeiros R, Passos G F, Vitor C E, Koepp J, Mazzuco T L, Pianowski L F. et al . Effect of two active compounds obtained from the essential oil of Cordia verbenacea on the acute inflammatory responses elicited by LPS in the rat paw.  Br J Pharmacol. 2007;  151 618-27
• 7 Passos G F, Fernandes E S, da Cunha F M, Ferreira J, Pianowski L F, Campos M M. et al . Anti-inflammatory and anti-allergic properties of the essential oil and active compounds from Cordia verbenacea. .  J Ethnopharmacol. 2007;  110 323-33
• 8 Peacock V E, Deinzer M L. The structures of humulene diepoxides found in hops and beer.  J Am Soc Brew Chem. 1989;  47 4-6
• 9 Guidance for Industry: Bioanalytical method validation, Center for Drug Evaluation and Research, United States Food and Drug Administration. Available at http://fda.gov/cder/guidance/index.html. Accessed in 2007
• 10 Fura A, Shu Y Z, Zhu M, Hanson R L, Roongta V, Humphreys W G. Discovering drugs through biological transformation: Role of pharmacologically active metabolites in drug discovery.  J Med Chem. 2004;  47 4339-51
• 11 Lam K C, Deinzer M L. Tentative identification of humulene diepoxides by capillary gas-chromatography chemical ionization mass-spectrometry.  J Agric Food Chem. 1987;  35 57-9