Penetration of antimicrobials to pulmonary epithelial lining fluid and muscle and impact of drug physicochemical properties determined by microdialysis

IntroductionThe objectives of this study were to characterize antimicrobial drug penetration into the pulmonary epithelial lining fluid (PELF) and extracellular fluid (ECF) of muscle in relation to physicochemical properties of the drugs (molecular mass, Log D, polar surface area and charge), using intrabronchial microdialysis. The series of drugs tested include gentamicin, sulfadiazine, cefquinome, minocycline and colistin.MethodsDrug concentrations were measured during 2 h of steady state plasma drug concentrations at therapeutic levels in anesthetized pigs. Microdialysis probes were positioned 2 to 4 cm distal to the tracheal bifurcature and in M. gluteobiceps and were calibrated by retrodialysis by drug.ResultsMean AUCPELF/PLASMA(fu) and mean AUCMUSCLE/PLASMA(fu) ratios were respectively for gentamicin (0.8, 0.7), sulfadiazine (1.1, 0.7), cefquinome (1.3, 1.5) minocycline (1.6, 0.7) and colistin (0.26, 0.12). The penetration of drugs into PELF (r2 = 0.55–0.77, p = 0.0004–0.0089) and ECF of muscle (r2 = 0.39–0.53, p = 0.0108–0.0397) was positively correlated to Log D, whereas molecular mass, polar surface area and charge were negatively correlated to drug penetration. Sulfadiazine, gentamicin, cefquinome and colistin had similar penetration ratios into PELF and ECF of muscle, ranging from 0.12 to 1.50.DiscussionIn conclusion, drug penetration into PELF and ECF of muscle is correlated to mass, lipophilicity, polarity and charge of the drugs. Drug partition into ECF of muscle and PELF are similar for the passively transported drugs gentamicin, sulfadiazine, cefquinome and colistin, whereas minocycline appears to be actively transported into PELF.