通过喹诺酮抗生素与磷脂膜的相互作用预测肺泡巨噬细胞单层的体外摄取

目的;预测肺泡巨噬细胞单层的体外摄取.方法:以培养的肺泡巨噬细胞单层为体外模型,用磷脂膜色谱,脂质体/水系统评价药物与磷脂膜的相互作用,分别表示为lg k_(1AM),lg D_(L B,7.4),用正辛醇/水系统测定参考的疏水性参数(lg D_(O/B,7.4).结果:lg D_(L B,7.4)(r~2=0.93)比lg D_(O B,7.4)(r~2=0.65)具有与lg k_(1AM)更显著的相关性.lg k_(1AM)和lg D_(L B,7.4)均 比lg D_(O/B,7.4)与细胞内药物的蓄积度有更好的相关性.但对于由5个两性喹酮抗生素和奎尼丁组成的受试集合,三者均与药物进入细胞内的速度具有相近的显著的正相关性.结论:磷脂膜色谱和脂质体/水系统给出相似的亲脂性测量尺度,且均与正辛醇/水系统区别有显著性.与疏水性参数相比,膜亲和性是更有效的肺泡巨噬细胞内药物蓄积和结合的预测参数.

Interactions between quinolone antibiotics and phospholipid membrane for prediction of alveolar macrophage uptake in vitro

AIM: To compare the effectiveness of the different parameters for predicting alveolar macrophage (AM) uptake, interactions between quinolones, including two amphipathic bases, and phospholipid membrane were evaluated by three different membrane-like systems. METHODS: AM cells were isolated, cultured as confluent monolayers, then incubated with drug solution at 37 degrees C. At designated time points, uptake was terminated by aspirating solution, followed by rinsing, cell lysis, a nd analysis of drug and protein concentrations. Immobilized artificial membrane (IAM) chromatography and liposome/buffer system were used to determine interactions with phospholipid membrane, expressed as lipophilicity indices, lg k(IAM) and lg D(L/B,7.4), respectively. An n-octano l/buffer system was also employed as the reference hydrophobicity, lg D(O/B,7.4)4. RESULTS: For the tested set, lg k(IAM) correlated more significantly with lg D(L/B,7.4) (r2 = 0.93) than with lgD(O/B,7.4) (r2 = 0.65). There were better correlations between either lg k(IAM) or lg D(L/B,7.4) and the extent of accumulation in AM than did lg DO/B,7.4 (r2 = 0.89, 0.92, and 0.67, respectively). Correlations obtained using lg k(IAM), lg D(L/B,7.4), and lg D(O/B,7.4) were comparable when regressed against the logarithm of influx rate into AM f or a set consisting of five amphoteric quinolones and quinidine. CONCLUSION: Liposome/buffer system and IAM chromatography could provide nearly similar scale of lipophilicity measurement, both distinct from n-octanol/buffer system. Accumulation by AM was better described by lg k(IAM) or lg D(L/B,7.4) than lg D(O/B,7.4), and the passive diffusion was principal form during drugs transported across AM membrane.