Pharmacokinetics And Investigation Of The Anxiolytic-Like Effect Of Mitragynine In Rats
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Date
2016-03
Authors
Imad Hazim Al Ganaby, Ammar
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Journal ISSN
Volume Title
Publisher
Universiti Sains Malaysia
Abstract
Mitragyna speciosa Korth (Rubiaceae) is an indigenous tree found in the Northern Malaysian Peninsula and in Southern Thailand. The principal alkaloid of this plant, Mitragynine (MG), has been reported to be responsible for most of its pharmacological properties. Doses of MG employed in most pharmacological studies vary greatly, which suggests that the selection of these doses was possibly carried out empirically without proper scientific basis. However, recent studies revealed that large dose variation was due but not limited, to MG physicochemical properties. Since pharmacokinetic evaluation is an essential component in the dose selection process, work was undertaken to determine MG pharmacokinetic properties such as dose proportionality, accumulation, plasma protein binding and tissue distribution in rats. The effects of MG on anxiety-related behaviours in rats and the possible involvement of opioidergic, GABAergic and dopaminergic pathways in the observed MG effects were also investigated in this study. A HPLC-UV method for the determination of MG levels in plasma and tissues was developed and validated. This method (plasma LOQ: 39 ng/ml; tissues LOQ: 50 ng/ml) was applied to determine MG concentrations in samples obtained from pharmacokinetic, tissue distribution and protein binding studies. In dose proportionality studies, MG exhibited linear pharmacokinetic properties (20-40 mg/kg), while non-linear pharmacokinetics were encountered at doses higher than 40 mg/kg. This study provided the basis to select a dosage of 20 mg/kg for MG multiple-dose pharmacokinetic evaluation. Repeated administrations of MG (20 mg/kg x 2 x 7 days) resulted in moderate drug accumulation in rats (Rac: 1.7). MG exposure parameters after multiple administrations were predictable since MG linear kinetics was observed in this dose range (linearity factor: 1.0). In the tissue distribution study, MG was mainly found in the liver, lung and kidney and less in heart and brain tissues. The presence of MG in the rat brain tissue indicated its ability to cross the blood brain barrier (BBB) despite its high binding to rat plasma proteins (89-92%). This may explain MG psychotropic properties reported in the literature. MG anxiolytic-like effects were determined using open-field and elevated plus-maze tests in rats. These effects were observed 1 hr after oral administration of 10, 20 and 40 mg/kg MG in rats. The early anxiolytic-like effects of MG may be due, but not limited, to the rapid equilibrium of MG between plasma and brain. This study showed that MG had possibly exerted its anxiolytic-like effects by indirect modulation of GABAergic and dopaminergic systems through the activation of opioid receptors in brain regions involved in anxiety.
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Keywords
Pharmacokinetics