Open AccessEvaluation of the Stability, Bioavailability, and Hypersensitivity of the Omega-3 Derived Anti-Leukemic Prostaglandin: Δ12-Prostaglandin J3
Author(s) -
Avinash K. Kudva,
Naveen Kaushal,
Sonia Mohinta,
Mary J. Kennett,
Avery August,
Robert F. Paulson,
K. Sandeep Prabhu
Publication year - 2013
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0080622
Subject(s) - pharmacology , in vivo , bioavailability , chemistry , histamine , ex vivo , intraperitoneal injection , metabolite , medicine , in vitro , biology , biochemistry , microbiology and biotechnology
Previous studies have demonstrated the ability of an eicosapentaenoic acid (EPA)-derived endogenous cyclopentenone prostaglandin (CyPG) metabolite, Δ 12 -PGJ 3 , to selectively target leukemic stem cells, but not the normal hematopoietic stems cells, in in vitro and in vivo models of chronic myelogenous leukemia (CML). Here we evaluated the stability, bioavailability, and hypersensitivity of Δ 12 -PGJ 3 . The stability of Δ 12 -PGJ 3 was evaluated under simulated conditions using artificial gastric and intestinal juice. The bioavailability of Δ 12 -PGJ 3 in systemic circulation was demonstrated upon intraperitoneal injection into mice by LC-MS/MS. Δ 12 -PGJ 3 being a downstream metabolite of PGD 3 was tested in vitro using primary mouse bone marrow-derived mast cells (BMMCs) and in vivo mouse models for airway hypersensitivity. ZK118182, a synthetic PG analog with potent PGD 2 receptor (DP)-agonist activity and a drug candidate in current clinical trials, was used for toxicological comparison. Δ 12 -PGJ 3 was relatively more stable in simulated gastric juice than in simulated intestinal juice that followed first-order kinetics of degradation. Intraperitoneal injection into mice revealed that Δ 12 -PGJ 3 was bioavailable and well absorbed into systemic circulation with a C max of 263 µg/L at 12 h. Treatment of BMMCs with ZK118182 for 12 h resulted in increased production of histamine, while Δ 12 -PGJ 3 did not induce degranulation in BMMCs nor increase histamine. In addition, in vivo testing for hypersensitivity in mice showed that ZK118182 induces higher airways hyperresponsiveness when compared Δ 12 -PGJ 3 and/or PBS control. Based on the stability studies, our data indicates that intraperitoneal route of administration of Δ 12 -PGJ 3 was favorable than oral administration to achieve effective pharmacological levels in the plasma against leukemia. Δ 12 -PGJ 3 failed to increase histamine and IL-4 in BMMCs, which is in agreement with reduced airway hyperresponsiveness in mice. In summary, our studies suggest Δ 12 -PGJ 3 to be a promising bioactive metabolite for further evaluation as a potential drug candidate for treating CML.