title: Penetration of antimicrobials to pulmonary epithelial lining fluid and muscle and impact of drug physicochemical properties determined by microdialysis.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  Drug concentrations were measured during 2h of steady state plasma drug concentrations at therapeutic levels in anesthetized pigs. Microdialysis probes were positioned 2 to 4cm distal to the tracheal bifurcature and in M. gluteobiceps and were calibrated by retrodialysis by drug.
  
  
  RESULTS
  Mean 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 (r(2)=0.55-0.77, p=0.0004-0.0089) and ECF of muscle (r(2)=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.
  
  
  CONCLUSIONS
  In 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.
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Veterinary Pharmacology and Toxicology, Denmark. Electronic address: lisa@sund.ku.dk.
authors.forename: Lisa Amanda Holm
authors.initials: LA
authors.lastname: Rottbøll
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Veterinary Pharmacology and Toxicology, Denmark. Electronic address: cfr@sund.ku.dk.
authors.forename: Christian
authors.initials: C
authors.lastname: Friis
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*; D055598:Chemical Phenomena / Q000187:drug effects; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D017551:Microdialysis / Q000379:methods*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*; D013552:Swine; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D000890:Anti-Infective Agents
keywords: Antimicrobials; Colistin; Drug penetration; Extracellular fluid; Gentamicin; Methods; Microdialysis; Physicochemical characteristics; Pigs; Pulmonary epithelial lining fluid