Chlorpromazine and clozapine are both used to treat psychotic illnesses. However, patients taking chlorpromazine exhibit more adverse side effects than those taking clozapine, which may be attributed to nonspecific interactions with lipids in the plasma membrane. We used second harmonic generation (SHG) to monitor the adsorption of these two antipsychotics to artificial phospholipid membranes. SHG allowed us to detect adsorption of small molecule drugs without fluorescent labels or extrinsic tags, which could interfere with the adsorption of the drug to the membrane. Artificial phospholipid membranes mimic mammalian plasma membranes and allowed us to control (and increase stepwise) the complexity of the lipid bilayer. We varied head group charge, alkyl chain length, fluidity, and cholesterol content. We studied the antipsychotics under physiologically-relevant drug concentrations and pH conditions. At circumneutral pH conditions, clozapine is neutral in charge while chlorpromazine is cationic. Adsorption data were fit with the Langmuir model; binding constants and relative surface concentrations were determined and comparisons were made for the two drugs. The goal of our studies was to gain knowledge about how the structure of an antipsychotic impacted its membrane-binding properties and to aid in the understanding of the mechanism behind antipsychotic drug-plasma membrane interactions.

Quantifying adsorption of chlorpromazine and clozapine to phospholipid membranes using second-harmonic generation

2019 Spring National Meeting

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