title: A novel oral dosage formulation of the ginsenoside aglycone protopanaxadiol exhibits therapeutic activity against a hormone-insensitive model of prostate cancer.
abstract: This study focuses on determining the pharmacokinetics, biodistribution, and efficacy of the ginsenoside aglycone protopanaxadiol (aPPD) administered as a single agent in a novel oral dosage formulation. To obtain these data and to characterize the stability of aPPD, appropriate analytical assay development was carried out. The solubility and stability of aPPD were determined, and the compound was formulated for oral gavage. aPPD levels in blood and tissues following oral administration to nu/nu nude mice were determined using liquid chromatography-mass spectrometry/mass spectrometry. The efficacy of aPPD was determined upon oral administration to nu/nu nude mice bearing PC-3 human prostate cancer xenograft tumors. Immunohistochemical analysis of tumor tissues was performed to establish apoptotic indices and Ki-67 expression as markers of proliferation. The maximum solubility of aPPD in ethanol was 68.4 mg/ml. aPPD administered at a dose of 70 mg/kg yielded a T(max) of approximately 40 min and a C(max) value of 3.9 ± 1.4 μg/ml, and no toxicity was observed. aPPD accumulated largely in the stomach and small intestine and was also present in the brain. This dose engendered a significant delay in PC-3 tumor growth, an increase in apoptotic index, and a decrease in Ki-67 levels. We have shown that aPPD is a stable compound that can be formulated for oral gavage. Pharmacokinetic studies demonstrate the ability of this compound to be absorbed after oral administration. Future studies will assess the activity and pharmacokinetics of aPPD when administered in combination with standard chemotherapy.
authors.affiliation: The Prostate Centre at Vancouver General Hospital, British Columbia, Canada. alainmus@gmail.com
authors.forename: Alain Gulenga
authors.initials: AG
authors.lastname: Musende
authors.forename: Andy
authors.initials: A
authors.lastname: Eberding
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Wood
authors.forename: Hans
authors.initials: H
authors.lastname: Adomat
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.forename: Antonio
authors.initials: A
authors.lastname: Hurtado-Coll
authors.forename: William
authors.initials: W
authors.lastname: Jia
authors.forename: Marcel B
authors.initials: MB
authors.lastname: Bally
authors.forename: Emma S
authors.initials: ES
authors.lastname: Tomlinson Guns
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004339:Drug Compounding; D004355:Drug Stability; D036145:Ginsenosides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D013058:Mass Spectrometry; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D012502:Sapogenins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D052616:Solid Phase Extraction; D012995:Solubility; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D036145:Ginsenosides; D012502:Sapogenins; C062916:protopanaxadiol