JAC Advance Access originally published online on January 28, 2004
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Journal of Antimicrobial Chemotherapy (2004) 53, 506-511
© 2004 The British Society for Antimicrobial Chemotherapy
Effect of norepinephrine on cefpirome tissue concentrations in healthy subjects
1 Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics; 2 Institute of Pharmacology; 3 Department of Internal Medicine I, Division of Infectious Diseases and Chemotherapy; 4 Department of Internal Medicine II, Division of Intensive Care Medicine, University of Vienna Medical School, Allgemeines Krankenhaus; Waehringer Guertel 18–20, A-1090 Vienna, Austria
Received 6 October 2003; returned 17 November 2003; revised 28 November 2003; accepted 13 December 2003
Objectives: To test whether norepinephrine (NOR) affects tissue microcirculation and impairs plasma-to-tissue equilibration of antimicrobial agents.
Materials and methods: Eight healthy male volunteers were enrolled to an analyst-blinded, randomized, two-period two-sequence crossover study. A single intravenous dose of 2 g of cefpirome was administered simultaneously with starting a continuous infusion of NOR (0.16 µg/kg per min) or placebo (PL) over 180 min. The microdialysis technique was used for the assessment of unbound cefpirome concentrations in skeletal muscle tissue and subcutaneous adipose tissue. Free plasma concentrations were related to corresponding tissue concentrations. Haemodynamics were determined by the measurement of mean arterial blood pressure (MAP), heart rate and forearm blood flow (FBF).
Results: Area under the concentration–time-curve (AUC) values of cefpirome for interstitium and plasma were not significantly different between the PL and NOR groups (P > 0.47). Tissue penetration of cefpirome as described by the ratios of the AUCs from 0 to 180 min for tissue to the AUC values for plasma were 0.81 ± 0.34 for the PL group and 0.80 ± 0.26 for the NOR group (P > 0.05). Baseline values of MAP, heart rate and FBF were not significantly different between study days. MAP increased significantly following NOR administration from 73.3 ± 3.5 mmHg at baseline to 94.0 ± 5.2 mmHg during infusion (P = 0.017). NOR exerted no significant effects on FBF.
Conclusions: We have shown that intravenous administration of NOR does not exert a significant effect on peripheral blood flow and tissue penetration of cefpirome in healthy men. This might be attributed to systemic regulatory mechanisms, which probably fully compensate for major changes in blood flow in peripheral tissues.
Keywords: microdialysis, forearm blood flow, haemodynamics, pharmacokinetics
* Corresponding author. Tel: +43-1-40400-2981; Fax: +43-1-40400-2998; E-mail: christian.joukhadar{at}univie.ac.at
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