RESUMEN
INTRODUCTION: 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. DISCUSSION: 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.
Asunto(s)
Antiinfecciosos/química , Antiinfecciosos/metabolismo , Líquido Extracelular/metabolismo , Microdiálisis/métodos , Músculo Esquelético/metabolismo , Mucosa Respiratoria/metabolismo , Animales , Antiinfecciosos/administración & dosificación , Fenómenos Químicos/efectos de los fármacos , Líquido Extracelular/efectos de los fármacos , Femenino , Músculo Esquelético/efectos de los fármacos , Permeabilidad/efectos de los fármacos , Mucosa Respiratoria/efectos de los fármacos , Porcinos , Distribución Tisular/efectos de los fármacos , Distribución Tisular/fisiologíaRESUMEN
Recent intrabronchial microdialysis data indicate that the respiratory epithelium is highly permeable to drugs. Of concern is whether intrabronchial microdialysis disrupts the integrity of the respiratory epithelium and thereby alters drug penetration into the pulmonary epithelial lining fluid (PELF). The objective of this study was to investigate the effect of intrabronchial microdialysis on the integrity of the bronchial epithelium. Microdialysis sampling in PELF in proximal (n = 4) and distal bronchi (n = 4) was performed after intravenous inulin and florfenicol administration in anaesthetized pigs. Inulin was used as a marker molecule of permeability of the epithelium, and florfenicol was used as test drug. Bronchial tissue was examined by histopathology (distal and proximal bronchi) and gene expression analysis (RT-qPCR, proximal bronchi) at the termination of the experiment (6.5 hr). The microdialysis probe caused overt tissue trauma in distal bronchi, whereas no histopathological lesions were observed in proximal bronchi. A moderate up-regulation of the pro-inflammatory cytokines IL1B, IL6 and acute-phase reactant serum amyloid A was seen in proximal bronchi surrounding the microdialysis probes suggesting initiation of an inflammatory response. The observed up-regulation is considered to have limited impact on drug penetration during short-term studies. Inulin penetrated the respiratory epithelium in both proximal and distal bronchi without any correlation to histopathological lesions. Likewise, florfenicol penetration into PELF was unaffected by bronchial histopathology. However, this independency of pathology on drug penetration may not be valid for other antibiotics. We conclude that short-term microdialysis drug quantification can be performed in proximal bronchi without disruption of tissue integrity.