title: Pharmacokinetic and tissue distribution studies of 1,9-pyrazoloanthrone, a c-Jun-N-terminal kinase inhibitor in Wistar rats by a simple and sensitive HPLC method.
abstract: JNK pathway activates c-Jun(s) which are responsible for cell apoptosis; as a result, inhibitors of JNK pathway have the potential to prevent dopaminergic neurons from death and decrease the loss of dopamine in substantia nigra pars compacta (SNpc). Recent in-vitro studies show that 1,9-pyrazoloanthrone (1,9-P) a potent JNK-3 inhibitor prevents the apoptosis of dopaminergic cells of brain. In the present study we formulated liposomes to increase the bioavailability of 1,9-P in the brain and developed a simple, sensitive and selective high performance liquid chromatographic method and validated for the estimation of 1,9-P in Wistar rat plasma and tissue samples. Plasma and tissue samples were extracted by protein precipitation technique using acetonitrile (ACN) and rasagiline as the internal standards. Chromatography was performed on Hibar C18 column with mobile phase of ammonium acetate (10mM, pH 8.0 adjusted with ammonia) and ACN at a flow rate of 1mL/min. The lower limit of quantification of the developed method was found to be 2.0ng/mL and 4.0ng/g in plasma and tissue samples respectively. The liposomes of 1,9-P administered to animals at the dose equivalent to 15mg/kg orally demonstrated remarkable absorption into the systemic circulation with maximum concentration (∼7500ng/mL) within 2.0h. The order of the area under curve was found to be kidney>liver>brain>lungs>spleen>heart. The liposomes of 1,9-P were rapidly taken up into brain and showed a good brain concentration after 2.0h; sustenance up to 4.0h was achieved which is better than 1,9-P solution.
authors.affiliation: Department of Pharmacology, JSS College of Pharmacy, Ootacamund, JSS University, Mysore 643001, India. Electronic address: nilesh.ambhore@yahoo.in.
authors.forename: Nilesh Sudhakar
authors.initials: NS
authors.lastname: Ambhore
authors.affiliation: Department of Pharmaceutical Analysis, JSS College of Pharmacy, Ootacamund, JSS University, Mysore 643001, India.
authors.forename: Karthik
authors.initials: K
authors.lastname: Yamjala
authors.affiliation: Department of Pharmaceutical Analysis, JSS College of Pharmacy, Ootacamund, JSS University, Mysore 643001, India.
authors.forename: Shubhashri
authors.initials: S
authors.lastname: Mohire
authors.affiliation: Department of Pharmacology, JSS College of Pharmacy, Ootacamund, JSS University, Mysore 643001, India.
authors.forename: Kalidhindi Rama Satyanarayana
authors.initials: KR
authors.lastname: Raju
authors.affiliation: Department of Pharmacology, JSS College of Pharmacy, Ootacamund, JSS University, Mysore 643001, India.
authors.forename: Shashank
authors.initials: S
authors.lastname: Mulukutla
authors.affiliation: Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Vishakantha
authors.initials: V
authors.lastname: Murthy
authors.affiliation: Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, Ootacamund, JSS University, Mysore 643001, India.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Tondhawada
authors.affiliation: Department of Pharmacology, JSS College of Pharmacy, Ootacamund, JSS University, Mysore 643001, India.
authors.forename: Kannan
authors.initials: K
authors.lastname: Elango
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D008081:Liposomes / Q000493:pharmacokinetics; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution / Q000502:physiology*; D000095322:Anthrones
chemical_list: D000873:Anthracenes; D008081:Liposomes; D020928:Mitogen-Activated Protein Kinases; D047428:Protein Kinase Inhibitors; C004522:anthrone; D000095322:Anthrones
keywords: 1,9-Pyrazoloanthrone; HPLC method; Pharmacokinetics; Tissue distribution; Validation