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.

The aim of the present study was to investigate the antiatherosclerotic effect of active principle (FIIc) isolated from aqueous fruit pulp extract of Eugenia jambolana. Crude aqueous extract of E. jambolana was subjected to purification using chromatographic techniques which yielded purified active compound (FIIc). Purity of FIIc was tested by HPLC. Phytochemical investigation of FIIc by NMR, IR, and UV spectra showed that the purified compound is α-hydroxy succinamic acid. The streptozotocin- (STZ-) induced diabetic rats were fed atherosclerotic (Ath) diet containing 1.5 mL olive oil containing 8 mg (3, 20,000 IU) vitamin D2 and 40 mg cholesterol for 5 consecutive days. The STZ-induced diabetic rats receiving Ath diet were orally administered FIIc at doses of 10, 15, and 20 mg/kg, and results were compared with reference drug, that is, glibenclamide (600 μg/mg) and healthy control. 30-day treatment with FIIc resulted in significant (P < .001) improvement in blood glucose, serum lipid profile, apolipoproteins (Apo A1 and apoB100), and endothelial dysfunction parameters. Histomorphological studies also confirmed biochemical findings. Our results showed that FIIc has protective effect on hyperglycemia-induced atherosclerosis.

Anticancer efficacy of ginger phenolics (GPs) has been demonstrated in various in vitro assays and xenograft mouse models. However, only sub-therapeutic plasma concentrations of GPs were detected in human and mouse pharmacokinetic (PK) studies. Intriguingly, a significant portion of GPs occurred as phase II metabolites (mainly glucuronide conjugates) in plasma. To evaluate the disposition of GPs and understand the real players responsible for efficacy, we performed a PK and tissue distribution study in mice. Plasma exposure of GPs was similar on day 1 and 7, suggesting no induction or inhibition of clearance pathways. Both free and conjugated GPs accumulated in all tissues including tumors. While non-cytotoxicity of 6-ginerol glucuronide precluded the role of conjugated GPs in cell death, the free forms were cytotoxic against prostate cancer cells. The efficacy of ginger was best explained by the reconversion of conjugated GPs to free forms by β-glucuronidase, which is over-expressed in the tumor tissue. This previously unrecognized two-step process suggests an instantaneous conversion of ingested free GPs into conjugated forms, followed by their subsequent absorption into systemic circulation and reconversion into free forms. This proposed model uncovers the mechanistic underpinnings of ginger’s anticancer activity despite sub-therapeutic levels of free GPs in the plasma.

Diabetes is accompanied by lipid abnormalities, which contribute significantly to cardiovascular morbidity and mortality in diabetic patients. We previously demonstrated the potent antihyperglycemic activity of the active principle (fraction II from Sephadex LH 20 chromatography [LH II]) isolated from ethanolic seed extract of Eugenia jambolana in diabetic rabbits. In the present study, the efficacy of LH II was evaluated for its hypolipidemic activity in alloxan-induced mildly diabetic (MD) and severely diabetic (SD) rabbits. Phytochemical investigation of LH II by various structural spectra showed the presence of saturated fatty acid, Δ(5) lipid, and sterol. Oral administration of LH II (10 mg/kg of body weight) for 21 days resulted in improved glycemic control in both MD and SD rabbits. After treatment with LH II, serum total cholesterol, triglycerides, high-density lipoprotein cholesterol, and the total cholesterol/high-density lipoprotein cholesterol ratio were significantly improved. LH II also resulted in significant (P < .001) improvement in 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity and levels of total lipids and glycogen in both MD and SD rabbits. Thus, the present study demonstrates that LH II possesses potent hypolipidemic activity and efficacy in both MD and SD rabbits.