Relationship between serum and free interstitial concentrations of cefodizime and cefpirome in muscle and subcutaneous adipose tissue of healthy volunteers measured by microdialysis

Microdialysis is a suitable method to monitor unbound concentrations of antimicrobial drugs in the interstitial tissue space which is the site of many infections. The aim of this investigation was to examine whether free tissue levels of cefodizime (81% plasma protein binding) and cefpirome (10% plasma protein binding) in muscle and subcutaneous adipose tissue of healthy volunteers obtained by microdialysis are consistent with the extent of their respective plasma protein binding. Healthy volunteers were given cefodizine and cefpirome at a single intravenous 2-g dose in a randomized crossover design. Microdialysis probes were inserted into a medial vastus muscle and into the periumbilical subcutaneous layer. After calibration of the probe, samples of serum and microdialysis fluid were obtained and drug concentrations were measured using a microagar diffusion-bioassay. There was a reasonable agreement between plasma protein binding data and the tissue penetration of both cephalosporins (AUC0-infinity tissue, free/AUC0-infinity serum, total-ratios) into the interstitial fluid of the muscle tissue, but not for the subcutaneous tissue layer. Furthermore, the serum and tissue concentrations of both drugs were fitted to an open two-compartment body model. The measured free-tissue concentrations were compared with calculated unbound concentrations in the peripheral compartment. Good agreement was observed for the free muscle concentrations, but unbound concentrations in the subcutaneous tissue was somewhat higher (cefpirome) or lower (cefodizime) than predicted. This may be due to the different lipophilicities of the two compounds.
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