LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Portugal.
INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal; IINFACTS, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Gandra, Portugal.
Eur J Pharm Biopharm. 2018 Aug;129:204-214. doi: 10.1016/j.ejpb.2018.05.036. Epub 2018 May 30.
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.
甲硝唑是一种具有抗菌和抗原生动物活性的咪唑衍生物。尽管具有治疗功效，但仍有多项研究致力于开发毒性更低的新型咪唑衍生物。鉴于药物-膜相互作用是药物药代动力学和药效学特性的关键因素，本工作旨在深入了解甲硝唑在磷脂膜内的结构-毒性关系。为此，使用由二棕榈酰磷脂酰胆碱组成的脂质膜模型（脂质体和单层膜）。实验技术（分配系数的测定和朗缪尔等温线测量）与分子动力学模拟相结合。评估了不同的 pH 值和脂质相，以便更好地外推到体内条件。甲硝唑的分配取决于 pH 值和双相系统（辛醇/水或 DPPC/水系统）。在 pH 值 1.2 时，甲硝唑具有亲水性。在 pH 值 7.4 时，甲硝唑会扰乱磷脂的有序性和堆积。对于这种毒性作用，甲硝唑侧链上的羟基基团通过与嵌入膜内的水以及与磷酸基团和磷脂的非极性链相互作用至关重要。
