Pharmacokinetics and Antihypertensive effect of linalool is improved after incorporation in β‐cyclodextrin as a drug delivery system
Authors: Camargo Samuel Flavia , Medeiros Carla Fiama , Santos Valdeene Vieira , Quintans-Júnior Lucindo José , Azeredo Francine Johansson , Silva Darizy Flavia 
Published: April 2020

Linalool (LIN) is a monoterpene alcohol present in some aromatic medicinal plants with biological activities that can impact cardiovascular disease. Previous studies from our research group have shown that LIN has antihypertensive activity, but as an essential oil it has some administration restrictions. The study aimed to investigate the pharmacokinetics (PK) and cardiovascular effects of LIN complexed with beta‐cyclodextrin (LIN/β‐CD) as a potential antihypertensive drug. All the experiments were conducted in accordance with FASEB statement of principles for the use of animals in research and education and approved by the ethics committee under the protocol CEUA‐ICS/UFBA n° 085/2015. For PK studies, LIN and LIN/β‐CD were administered to male normotensive wistar rats orally and LIN plasma concentrations were validated by HPLC‐UV. The individual and mean PK parameters of elimination rate, absorption rate, clearance, volume of distribution, half‐life, mean residence time, absolute bioavailability and relative bioavailability were estimated for LIN free or complexed form. For the cardiovascular experiments, spontaneously hypertensive rats (SHR) and wistar were used. Rats were randomly divided into 3 groups, each treated daily for 60 days, in the following manner: group 1 (vehicle solution); group 2 (LIN; 50 mg/kg/day); group 3 group (LIN/β‐CD; 50 mg/kg/day). Blood pressure, daily body weight and vascular reactivity were studied. The results of PK parameters showed that bioavailability of the LIN/β‐CD was approximately 20‐fold higher compared to LIN, after oral administration. Population modeling studies demonstrated that LIN/β‐CD had less tissues distribution compared to non‐complexed form, consequently remaining in the bloodstream or more irrigated organ and tissues. In addition, LIN/β‐CD, but not LIN, was able to induce acute hypotensive effect after oral administration. Furthermore, during the 60 days of chronic treatment, SHR treated with vehicle (192 ± 2.5 mmHg, p<0.05; 40th day) demonstrated progressive increase in mean arterial pressure compared to wistar normotensive rats (103 ± 5 mmHg, 40th day). However, the blood pressure of the SHR treated by LIN/β‐CD was significantly reduced during the treatment, presenting similar levels to the normotensive healthy animals (113 ± 5 mmHg; 40th day). This antihypertensive effect induced by complexed form was not observed with linalool free (167 ± 8 mmHg 40th day). Vascular reactivity assays using superior mesenteric artery rings demonstrated that LIN/β‐CD or LIN ameliorated the vascular function of SHR, increasing vasodilator responsiveness and reducing sensitivity to the sympathetic agonist. Taking together, our results suggested that incorporation of linalool into β‐cyclodextrin improved the bioavailability and antihypertensive effect of this monoterpene, making it a possible new pharmaceutical formulation for the treatment of hypertension in the future.

Support or Funding Information

FIOCRUZ, National Council for Scientific and Technological Development (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior ‐ Brasil (CAPES).