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


CONCLUSIONS
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.
Sun
Jin
J
Department of Pharmaceutics, Shenyang Pharmaceutical University, Shen yang 110016, China. sunjin66@21cn.com
Deguchi
Yoshiharu
Y
Chen
Ji-Min
JM
Zhang
Ru-Hua
RH
Morimoto
Kazuhiro
K
D042462:4-Quinolones; D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D008081:Liposomes; D016676:Macrophages, Alveolar / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008567:Membranes, Artificial; D010743:Phospholipids / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D042462:4-Quinolones; D000890:Anti-Infective Agents; D008081:Liposomes; D008567:Membranes, Artificial; D010743:Phospholipids