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    Metronidazole within phosphatidylcholine lipid membranes: New insights to improve the design of imidazole derivatives

    Year: 2018

    Journal: Eur. J. Pharm. Biopharm., Volume 129, AUG, page 204–214

    Authors: Lopes-de-Campos, Daniela; Nunes, Claudia; Sarmento, Bruno; Jakobtorweihen, Sven; Reis, Salette

    Organizations: Fundacao para a Ciencia e Tecnologia (FCT) [PD/BD/105957/2014, IF/00293/2015]; FCT through the FCT PhD Programmes; Programa Operacional Capital Humano (POCH); BiotechHealth Programe (Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences); European Union (FEDER) [POCI/01/0145/FEDER/007265]; National Funds (FCT/MEC, Fundacao para a Ciencia e Tecnologia and Ministerio da Educacao e Ciencia) [PT2020 UID/QUI/50006/2013]

    Keywords: Metronidazole; Imidazole derivatives; Structure-toxicity relationship; Liposomes; Monolayers; Molecular dynamics simulations; Drug design

    Metronidazole is a imidazole derivative with antibacterial and antiprotozoal activity. Despite its therapeutic efficacy, several studies have been developing new imidazole derivatives with lower toxicity. Considering that drug-membrane interactions are key factors for drugs pharmacokinetic and pharmacodynamic properties, the aim of this work is to provide new insights into the structure-toxicity relationship of metronidazole within phosphatidylcholine membranes. For that purpose, lipid membrane models (liposomes and monolayers) composed of dipalmitoylphosphatidylcholine were used. Experimental techniques (determination of partition coefficients and Langmuir isotherm measurements) were combined with molecular dynamics simulations. Different pHs and lipid phases were evaluated to enable a better extrapolation for in vivo conditions. The partition of metronidazole depends on the pH and on the biphasic system (octanol/water or DPPC/water system). At pH 1.2, metronidazole is hydrophilic. At pH 7.4, metronidazole disturbs the order and the packing of phospholipids. For this toxic effect, the hydroxyl group of the side chain of metronidazole is crucial by interacting with the water embedded in the membrane and with the phosphate group and the apolar chains of phospholipids.
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