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

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.

Keywords: bioavailability; geraniol; gut; pharmacokinetics; xenobiotic-metabolizing enzymes.

FIGURE 1

Chemical structure of geraniol.

FIGURE 2

High performance liquid chromatography (HPLC) chromatograms for (A) a physical mixture of 6.4 μg/ml geraniol and 8.4 μg/ml carbazole used as internal standard (IS), (B) a blank blood sample and (C–E) geraniol extracted from blood samples at the concentrations 3.9 μg/ml (C), 15.4 μg/ml (D) and 38.6 μg/ml (E).

FIGURE 3

Permeation kinetics of 500 μM geraniol across the Millicell filters alone (filter) or covered by monolayers obtained from NCM460 cells. The permeations were analyzed from the apical to basolateral compartments and from the basolateral to apical compartments. In all cases analyzed, the cumulative amounts in the receiving compartments were linear over time within 45 min (r ≥ 0.994, P ≤ 0.0001). All data are reported as mean ± SE of four independent experiments.

FIGURE 4

Elimination profile of geraniol after 12.5 mg intravenous infusion to rats. Data are expressed as the mean ± SE of four independent experiments. The elimination followed an apparent first order kinetics, confirmed by the semilogarithmic plot reported in the inset (n = 5, r = 0.963, P < 0.0001). The half-life of geraniol was calculated to be 12.5 ± 1.5 min.

FIGURE 5

Blood geraniol concentrations (μg/mL) within 180 min after intravenous infusion (iv) or oral administration of a 12.5 mg dose to rats. Data are expressed as the mean ± SE of four independent experiments. The oral formulations consisted of emulsified geraniol or a suspension of geraniol adsorbed in vegetable fiber.

FIGURE 6

Area Under Concentration values (AUC) referred to the bloodstream of rats obtained after intravenous infusion or oral administration of a 12.5 mg dose of geraniol. Data are expressed as the mean ± SE of four independent experiments. ^∗P > 0.05 versus intravenous; ^∗∗P < 0.001 versus intravenous.

FIGURE 7

Geraniol concentrations (μg/mL) detected in the CSF of rats after oral administration of a 12.5 mg dose as emulsified formulation. Data are expressed as the mean ± SE of at least four independent experiments.