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

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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 (10 mM, pH 8.0 adjusted with ammonia) and ACN at a flow rate of 1 mL/min. The lower limit of quantification of the developed method was found to be 2.0 ng/mL and 4.0 ng/g in plasma and tissue samples respectively. The liposomes of 1,9-P administered to animals at the dose equivalent to 15 mg/kg orally demonstrated remarkable absorption into the systemic circulation with maximum concentration (˜7500 ng/mL) within 2.0 h. 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 2.0 h; sustenance up to 4.0 h was achieved which is better than 1,9-P solution.

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