Geraniol Pharmacokinetics, Bioavailability and Its Multiple Effects on the Liver Antioxidant and Xenobiotic-Metabolizing Enzymes.

Barbara Pavan,Moreno Paolini,Luca Ferraro,Luigia De Fazio,Antonietta Comparone,Alessandro Dalpiaz,Fabio Vivarelli,Maria C Valerii,Enzo Spisni,Sarah Beggiato,Luca Marani,Donatella Canistro

doi:10.3389/fphar.2018.00018

Barbara Pavan, Moreno Paolini + Show 10 more

Open Access

https://doi.org/10.3389/fphar.2018.00018

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Abstract

Geraniol is a natural monoterpene showing anti-inflammatory, antioxidant, neuroprotective and anticancer effects. No pharmacokinetic and bioavailability data on geraniol are currently available. We therefore performed a systematic study to identify the permeation properties of geraniol across intestinal cells, and its pharmacokinetics and bioavailability after intravenous and oral administration to rats. In addition, we systematically investigated the potential hepatotoxic effects of high doses of geraniol on hepatic phase I, phase II and antioxidant enzymatic activities and undertook a hematochemical analysis on mice. Permeation studies performed via HPLC evidenced geraniol permeability coefficients across an in vitro model of the human intestinal wall for apical to basolateral and basolateral to apical transport of 13.10 ± 2.3 × 10-3 and 2.1 ± 0.1⋅× 10-3 cm/min, respectively. After intravenous administration of geraniol to rats (50 mg/kg), its concentration in whole blood (detected via HPLC) decreased following an apparent pseudo-first order kinetics with a half-life of 12.5 ± 1.5 min. The absolute bioavailability values of oral formulations (50 mg/kg) of emulsified geraniol or fiber-adsorbed geraniol were 92 and 16%, respectively. Following emulsified oral administration, geraniol amounts in the cerebrospinal fluid of rats ranged between 0.72 ± 0.08 μg/mL and 2.6 ± 0.2 μg/mL within 60 min. Mice treated with 120 mg/kg of geraniol for 4 weeks showed increased anti-oxidative defenses with no signs of liver toxicity. CYP450 enzyme activities appeared only slightly affected by the high dosage of geraniol.

Highlights

Geraniol (3,7-dimethylocta-trans-2,6-dien-1-ol) is an acyclic monoterpene (Figure 1) with a water solubility of 100 mg/L at 25◦C and an n-octanol/water partition coefficient of 2.65 (Turina et al, 2006)
The first step of our work consisted of permeability studies evaluating the bidirectional transport of geraniol across an in vitro model of human intestinal wall, i.e., NCM460 cell monolayers
The permeation profiles referred to both directions of geraniol across the Millicell filters alone (Filter) or covered with monolayers of NCM460 cells are reported in Figure 3 showing that the cumulative amounts of geraniol in the receiving compartments have a linear profile over 45 min in all cases (r ≥ 0.994, P ≤ 0.0001), indicating constant permeation conditions within this range of time

Summary

Introduction

Geraniol (3,7-dimethylocta-trans-2,6-dien-1-ol) is an acyclic monoterpene (Figure 1) with a water solubility of 100 mg/L at 25◦C and an n-octanol/water partition coefficient of 2.65 (Turina et al, 2006). Oral administration of geraniol supported the ability of dopaminergic neurons to survive free radical injury by inducing the production of antioxidant enzymes and reducing the expression of apoptotic markers (Rekha et al, 2014). These properties indicate that geraniol is a natural compound potentially able to prevent the progression of Parkinson’s disease and other neurodegenerative disorders (Rekha et al, 2014) and to serve as a therapeutic agent in the treatment of a wide range of cancers, including lung, pancreatic, hepatic and kidney tumors (Cho et al, 2016). The potential therapeutic effects of geraniol have major clinical implications as this essential oil component is classified in the generally-recognized-as-safe (GRAS) category (Lapczynski et al, 2008)

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