A Differential Scanning Calorimetry Study of the Interaction of the Antimalarial Agent Halofanthrine with Dipalmitoyl Phosphatidyl Choline Bilayers.

Abstract

The influence of the antimalarial agent halofanthrine on the phase transition temperature (Tm) of dipalmitoyl phosphatidyl choline (DPPC) liposomes was investigated by differential scanning calorimetry (DSC). The effects of increasing drug content and varying pH conditions (to give predominantly charged and uncharged states of the drug) on the interaction were considered and compared with those caused by structurally related antimalarials, mefloquine and quinine, under similar conditions. Increasing concentrations of halofanthrine resulted in the gradual disappearance of the original transition endotherm and the appearance of a new drug-induced endotherm at a lower temperature and with a decreased enthalpy of transition. Qualitatively similar observations were made at different pH conditions, suggesting little difference in the mode of interaction of charged and uncharged halofanthrine molecules with DPPC. Increasing concentrations of mefloquine and quinine also caused a decline in Tm but neither drug-induced endotherms was associated with a decreased enthalpy of transition. The results indicate that halofanthrine, unlike mefloquine and quinine, intercalates in the hydrophobic interior of the phospholipid. Its localization among the fatty acid side chains of the phospholipid is possibly related to its greater hydrophobic character compared to mefloquine and quinine. The disruption of phospholipid packing and the consequential effects on membrane permeability and integrity may be relevant to the greater in vitro antimalarial activity of halofanthrine and should be considered in any delibration of its pharmacodynamic action.