Glycyrrhizin-Assisted Transport of Praziquantel Anthelmintic Drug through the Lipid Membrane: An Experiment and MD Simulation

Abstract

Praziquantel (PZQ) is one of the most widespread anthelmintic drugs. However, the frequent insufficient application of PZQ after oral administration is associated with its low solubility, penetration rate, and bioavailability. In the present study, the permeation of PZQ through a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membrane was investigated to probe glycyrrhizin-assisted transport. Glycyrrhizin (or glycyrrhizic acid, GA), a natural saponin, shows the ability to enhance the therapeutic activity of various drugs when it is used as a drug delivery system. However, the molecular mechanism of this effect is still under debate. In the present study, the transport rate was measured experimentally by a parallel artificial membrane permeation assay (PAMPA) and molecular dynamics (MD) simulation with DOPC lipid bilayers. The formation of the noncovalent supramolecular complex of PZQ with disodium salt of GA (Na2GA) in an aqueous solution was proved by the NMR relaxation technique. PAMPA experiments show a strong increase in the amount of the penetrating praziquantel molecules in comparison with a saturated aqueous solution of pure drug used as a control. MD simulation of PZQ penetration through the bilayer demonstrates an increase in permeability into the membrane in the presence of a glycyrrhizin molecule. A decrease in the free energy barrier in the middle of the lipid bilayer was obtained, associated with the hydrogen bond between PZQ and GA. Also, GA reduces the local bilayer surface resistance to penetration of PZQ by rearranging the surface lipid headgroups. This study clarifies the mechanism of increasing the drug’s bioavailability in the presence of glycyrrhizin.

pH-Sensitive Glycyrrhizin Based Vesicles for Nifedipine Delivery

“…Apparently, same as neutral GA molecules, GA ions can form stable complexes with nifedipine in water, which can increase their solubility and facilitate its transport to and through a cellular membrane. A similar effect of GA has been recently shown for praziquantel [42].…”

Mechanism of the enhancing effect of glycyrrhizin on nifedipine penetration through a lipid membrane

“…All simulations were carried out using the GROMACS package v. 2016. We used the same parameter sets and protocol as in our previous papers [28] , [32] . Berger’s DOPC lipids [42] were employed in GROMOS53a6 forcefield.…”

“…The effective membrane permeability P eff was calculated similarly to previously published works [32] and a number of other works [37] , [48] . The method relies on the general diffusion theory of transport in the diffusional limit, where the average flow rate is proportional to the thermodynamic driving force [49] .…”

“…The membrane modifying ability of GA has been described recently [28] , [29] , [30] , [31] , [32] , [33] . Thus, an additional mechanism of GA’s influence on the drug bioavailability was suggested, namely, an increase in membrane permeability.…”

Glycyrrhizin: An alternative drug for the treatment of COVID-19 infection and the associated respiratory syndrome?

“…Therefore, the drug can be used as nonselective delivery vector for a variety of drugs (Selyutina & Polyakov, 2019;Su et al, 2017). A nice example has been reported recently with the GLR-mediated enhanced delivery of the anti-helminthic drug praziquantel, showing that the self-association of GLR molecules plays an important role in increasing the solubility and transport to the cell surface of praziquantel (Kim et al, 2019). A water-soluble preparation of disodium glycyrrhizinate micelles with inclusion of praziquantel proved to be a good anthelmintic agent in vitro and in vivo, owing to a significant improvement of the bioavailability of praziquantel (Avgustinovich et al, 2019;Meteleva et al, 2018).…”