title: 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 conductingin vitroassays 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.
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA. vmukkavilli@gsu.edu.
authors.forename: Rao
authors.initials: R
authors.lastname: Mukkavilli
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA. ychnjcpu@gmail.com.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA. drreenu10@gmail.com.
authors.forename: Reenu
authors.initials: R
authors.lastname: Singh Tanwar
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA. afghareeb80@gmail.com.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Ghareeb
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA. latika.luthra@yahoo.com.
authors.forename: Latika
authors.initials: L
authors.lastname: Luthra
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA. raneja@gsu.edu.
authors.forename: Ritu
authors.initials: R
authors.lastname: Aneja
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D020939:Zingiber officinale / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007654:Ketoconazole / Q000008:administration & dosage; D008099:Liver / Q000737:chemistry*; D051379:Mice; D010636:Phenols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D064209:Phytochemicals / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D010936:Plant Extracts / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D012995:Solubility
chemical_list: D010636:Phenols; D064209:Phytochemicals; D010936:Plant Extracts; D007654:Ketoconazole
keywords: biopharmaceutical drug disposition classification system; ginger; liquid chromatography tandem mass spectrometry; microsomal stability; pharmacokinetics; solubility