Absorption, Metabolic Stability, and Pharmacokinetics of Ginger Phytochemicals

Abstract

We have previously demonstrated promising anticancer efficacy of orally-fed whole ginger extract (GE) in preclinical prostate models emphasizing the importance of preservation of the natural “milieu”. Essentially, GE primarily includes active ginger phenolics viz., 6-gingerol (6G), 8-gingerol (8G), 10-gingerol (10G), and 6-shogaol (6S). However, the druglikeness properties of active GE phenolics like solubility, stability, and metabolic characteristics are poorly understood. Herein, we determined the physicochemical and biochemical properties of GE phenolics by conducting in vitro assays and mouse pharmacokinetic studies with and without co-administration of ketoconazole (KTZ). GE phenolics showed low to moderate solubility in various pH buffers but were stable in simulated gastric and intestinal fluids, indicating their suitability for oral administration. All GE phenolics were metabolically unstable and showed high intrinsic clearance in mouse, rat, dog, and human liver microsomes. Upon oral administration of 250 mg/kg GE, sub-therapeutic concentrations of GE phenolics were observed. Treatment of plasma samples with β-glucuronidase (βgd) increased the exposure of all GE phenolics by 10 to 700-fold. Co-administration of KTZ with GE increased the exposure of free GE phenolics by 3 to 60-fold. Interestingly, when the same samples were treated with βgd, the exposure of GE phenolics increased by 11 to 60-fold, suggesting inhibition of phase I metabolism by KTZ but little effect on glucuronide conjugation. Correlating the in vitro and in vivo results, it is reasonable to conclude that phase II metabolism seems to be the predominant clearance pathway for GE phenolics. We present evidence that the first-pass metabolism, particularly glucuronide conjugation of GE phenolics, underlies low systemic exposure.

[10]-gingerol induces apoptosis and inhibits metastatic dissemination of triple negative breast cancer in vivo

“…However, [10]-gingerol half-life was approximately 2h and maximum plasma concentration was low (estimated at 0.53 ± 0.4 μg/ml, ∼ 1.5 μM), especially due to its diminished amount in the extract. Similarly, Mukkavilli and colleagues [ 27 ] recently reported that [10]-gingerol is stable and suitable for oral administration in mice but that it has poor solubility in plasma and rapid clearance in vivo . Together these studies suggested that tumour inhibition may not be achievable in vivo when [10]-gingerol is administered orally.…”

“…Given the high tolerability and relatively short half-life of [10]-gingerol (∼2 h) [ 31 ], we are currently investigating whether greater efficacy against established brain metastases could be achieved by increasing the dose and/or frequency of treatment. Moreover, in light of the relatively low plasma concentrations achieved in human or mouse by oral administration (due in part to limited absorption and solubility), greater efficacy of [10]-gingerol against CTCs or disseminated tumour cells could potentially be achieved by improving absorption via better oral formulations and/or by strategies to improve the bioavailability of free [10]-gingerol in plasma as recently proposed [ 27 ].…”

Ginger: Panacea or Consumer’s Hype?

“…This was demonstrated by a study on mice treated with 250 mg/kg of ginger extract. The study monitored the main active components of ginger in the free form, revealing very low seric levels [21]. Also remarkable are the different absorption kinetics observed for each one of the components.…”

LC–MS/MS analysis of puerarin and 18β‐glycyrrhetinic acid in human plasma after oral administration of Samso‐eum and its application to pharmacokinetic study

“…Naringin was metabolized to naringenin by human intestinal bacteria (Yu, Jang, Kang, Sung, & Kim, 1997); ginsenoside Rb1 might have been metabolized to bioactive compound(s) by exo-β-D-glucosidase(s) produced from the intestinal bacteria (Jang, Lee, Hyun, & Kim, 2012). Ginger extract included active ginger phenolic compounds: 6-gingerol and 6-shogaol (Mukkavilli et al, 2017). Platycodin D was hydrolyzed rapidly in fecal lysate and decreased by 64% within 30 min (Shan et al, 2015).…”