SUMATRIPTAN/POLOXAMER INTERACTIONS WITH MODEL MEMBRANES BY MOLECULAR DYNAMICS SIMULATIONS

I. WOOD; D. ARAUJO; M. PICKHOLZ

Pisa

Conferencia; 3rd Conference on Innovationin Drug Delivery / Advances in Loccal Drug Delivery APGI; 2013

APGI

Purpose: Sumatriptan ? an antimigraine drug, specially designed as serotonin receptor agonist ? has a low lipid/water partition coefficient. This fact hinders the drug crossing process through blood-brain barrier, to reach the central nervous system at clinical effective concentrations. In order to improve the sumatriptan efficacy, its incorporation in poloxamer- micelles is being proposed. Computer simulations were used in order to reveal, at the molecular level, the effects of polymers in model barriers in the presence of sumatriptan. Methods: Molecular Dynamics (MD) simulations were carried out through two different strategies: i) Atomistic MD simulations of sumatriptan in model membranes as function of its concentration and the pH of the system. ii) Coarse grain MD approach on the effects of three different poloxamers on model membranes in the presence of sumatriptan. Results: As a first step, we have studied the partition of sumatriptan into a model membrane at different concentrations. Results show that sumatriptan partition between water and the lipid head/water interface of these molecules, with no access to the hydrophobic core of the bilayer. On the other hand, the effects of the poloxamers on model membranes are strongly dependent on the size and lipophilicity of the polymer. Propylene oxide units are essentially found in the membrane core while the polyethylene oxides stay at the lipid/water interphase, modifying the fluidity of the bilayers and sumatriptan interactions with it. Conclusion: Results from extensive molecular dynamics simulations suggest that formulation of sumatriptan that includes poloxamer could help the drug to cross membrane barriers.