Complexation of teicoplanin and sulfobutylether-β-cyclodextrin: experimental and theoretical insights into the potential relevance of their molecular interaction to teicoplanin pharmacokinetics.

Abstract

Teicoplanin (TEIC) is widely used in clinical settings to treat serious bacterial infections. This lipoglycopeptide antimicrobial is characterized by a long elimination half-life because of high protein binding owing to its lipophilic side chain. We recently found that the blood concentration of TEIC was significantly decreased when posaconazole was concomitantly administered intravenously rather than orally. We hypothesized that sulfobutylether-β-cyclodextrin (SBE-β-CD), a pharmaceutical excipient contained in posaconazole injectable formulation, may be the potential contributor to this phenomenon. Here, we investigated the molecular interaction between TEIC and SBE-β-CD by theoretical and experimental strategies to examine this possibility and elucidate the underlying mechanisms. Nuclear magnetic resonance analysis confirmed the encapsulation of the TEIC hydrophobic tail by the SBE-β-CD hydrophobic cavity, thereby forming a complex with 1:1 stoichiometry and appreciable binding affinity. These findings were further supported by docking simulations and subsequent quantum chemical calculations. Non-covalent interaction analysis visualized the regions and features of their supramolecular interactions. Computational and in vitro studies highlighted the significant contribution of the TEIC hydrophobic side chain in its binding to human serum albumin. Our results collectively indicate that the direct molecular interaction, whereby the hydrophobic cavity of SBE-β-CD encapsulates most of the hydrophobic side chain of TEIC, can reduce TEIC protein binding and may consequently affect its pharmacokinetics.