Determination of Histamine H3-Receptor Antagonist Conessine in Wistar Rat Plasma by a Rapid and Sensitive RP-UFLC Method: Application to a Pharmacokinetic Study

Abstract

Objectives: Epidemiological data suggests the highest density of histamine H3-receptors (H3R) in basal ganglia of central nervous system (CNS) wherein they function as inhibitory auto-receptors and control the release of many neurotransmitters. Inhibition of H3R increases the turnover of neurotransmitters, especially dopamine in basal ganglia and could be beneficial to treat Parkinson’s disease. Methods: In this study, we formulated the brain targeting liposomes of conessine, a selective antagonist for H3R to increase bioavailability and developed and validated a rapid and sensitive reverse phase ultra-force liquid chromatographic (RP-UFLC) method and to quantitate conessine in Wistar rat plasma and tissue. Plasma and tissue samples were extracted by protein precipitation technique using ace-tonitrile (ACN) and aripiprazole as the internal standard. Chromatographic separation was performed on the Hibar C18 column with a mobile phase of Hexane Sulphonic acid (10 mM, pH 10.0 adjusted with ammonia) and methanol at a flow rate of 0.9 ml/min. Results: The lower limit of quantification of the developed method was 4.0 ng/ml and 6.0 ng/g in plasma and tissue samples, respectively. Liposomes of conessine (equivalent to 20 mg/kg) administered orally to animals, demonstrated remarkable absorption into the systemic circulation with maximum concentration (~8700 ng/ ml) within 2.0 h. The order of area under curve was found to be kidney> brain> liver> lungs> spleen> heart. Conclusion: The liposomes of conessine were rapidly taken up into the brain and showed a good brain concentration after 2.0 h; sustenance up to 4.0 h was achieved which is better than conessine solution.