The interaction of selective estrogen receptor modulators (SERMs) with lipid 
membranes has been measured at clinically relevant serum concentrations using 
the label-free technique of second harmonic generation (SHG). The SERMs 
investigated in this study include raloxifene, tamoxifen, and the tamoxifen 
metabolites 4-hydroxytamoxifen, N-desmethyltamoxifen, and endoxifen. Equilibrium 
association constants (Ka) were measured for SERMs using varying lipid 
compositions to examine how lipid phase, packing density, and cholesterol 
content impact SERM-membrane interactions. Membrane-binding properties of 
tamoxifen and its metabolites were compared on the basis of hydroxyl group 
substitution and amine ionization to elucidate how the degree of drug ionization 
impacts membrane partitioning. SERM-membrane interactions were probed under 
multiple pH conditions, and drug adsorption was observed to vary with the 
concentration of soluble neutral species. The agreement between Ka values 
derived from SHG measurements of the interactions between SERMs and artificial 
cell membranes and independent observations of the SERMs efficacy from clinical 
studies suggests that quantifying membrane adsorption properties may be 
important for understanding SERM action in vivo.