Binding of bisphosphonates (BPs) to plasma proteins was investigated in the 1990s as a pharmacokinetic issue in order to fully understand bio-distribution of BP drugs which are successfully used for the treatment of several bone-related diseases. It has been hypothesized that binding to these proteins occurs with low to moderate affinity despite of unfavorable hydrophilicity of BPs, and Ca2+ was identified as a strong catalyst of this binding. However, these studies mainly consisted in the separation and quantification of bound and unbound drug or protein fractions using chromatographic techniques without an outcome on the molecular level. Presented thermodynamic studies analyze the interactions of three N-BPs as well as their Ca2+ complexes with bovine serum albumine (BSA) by means of isothermal calorimetry. The studies reveal spontaneous enthalpy favored interactions of N-BPs (amino-containing BPs) with BSA, which are enhanced by the presence of Ca2+ ions up to ~15-fold, strongly depending on N-BP. Those are low affinity binding events, comparable to Ca2+ -N-BP interactions, which most likely occur at Ca2+ binding site(s). It is a first example of estimation of thermodynamic forces of interactions of free and calcium-bound N-BPs with albumin.
Keywords: BSA; aminobisphosphonates; calcium; isothermal titration calorimetry; thermodynamics.
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