RESUMEN
In the present pilot study we investigated the effect of food ingestion on target site pharmacokinetics of linezolid, the first clinically approved oxazolidinone. For this purpose we determined free concentrations of linezolid at steady state in the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue under fasting and non-fasting conditions in healthy volunteers (n = 9) by means of in vivo microdialysis. Ingestion of food led to a marked delay in the time to reach the peak concentration (T(max)), whereas the area under the concentration-time curve from 0 to 24 h (AUC(0-24 h)) remained unchanged. These data suggest that the rate of linezolid absorption is decreased by food intake. However, the overall extent of linezolid absorption and the distribution of linezolid were not affected. Tissue levels of linezolid appeared sufficiently high to eradicate pathogens with a minimum inhibitory concentration of Asunto(s)
Acetamidas/sangre
, Acetamidas/farmacocinética
, Antibacterianos/sangre
, Antibacterianos/farmacocinética
, Oxazolidinonas/sangre
, Oxazolidinonas/farmacocinética
, Acetamidas/administración & dosificación
, Tejido Adiposo/metabolismo
, Administración Oral
, Anciano
, Antibacterianos/administración & dosificación
, Líquido Extracelular/metabolismo
, Femenino
, Alimentos
, Humanos
, Absorción Intestinal
, Linezolid
, Masculino
, Microdiálisis
, Persona de Mediana Edad
, Músculo Esquelético/metabolismo
, Oxazolidinonas/administración & dosificación
, Proyectos Piloto
, Distribución Tisular
RESUMEN
The present study tested the ability of linezolid to penetrate soft tissues in healthy volunteers. Ten healthy volunteers were subjected to linezolid drug intake at a dose of 600 mg twice a day for 3 to 5 days. The first dose was administered intravenously. All following doses were self-administered orally. The tissue penetration of linezolid was assessed by use of in vivo microdialysis. In the single-dose experiments the ratios of the area under the concentration-time curve from 0 to 8 h (AUC0-8) for tissue to the AUC0-8 for free plasma were 1.4+/-0.3 (mean+/-standard deviation) and 1.3+/-0.4 for subcutaneous adipose and muscle tissue, respectively. After multiple doses, the corresponding mean ratios were 0.9+/-0.2 and 1.0+/-0.5, respectively. The ratios of the AUC from 0 to 24 h (AUC0-24) for free linezolid in tissues to the MIC were between 50 and 100 for target pathogens with MICs between 2 and 4 mg/liter. In conclusion, the present study showed that linezolid penetrates rapidly into the interstitial space fluid of subcutaneous adipose and skeletal muscle tissues in healthy volunteers. On the basis of pharmacokinetic-pharmacodynamic calculations, we suggest that linezolid concentrations in soft tissues can be considered sufficient to inhibit the growth of many clinically relevant bacteria.