JAC Advance Access published online on January 28, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh111
© 2004 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Department of Clinical
Pharmacology, Division of Clinical Pharmacokinetics;
* Corresponding author. E-mail: christian.joukhadar{at}univie.ac.at.
Received 6 October 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
Effect of norepinephrine on cefpirome tissue concentrations
in
healthy subjects
2 Department of Internal Medicine
I, Division of Infectious Diseases and Chemotherapy;
3 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
4 Department of Clinical
Pharmacology, Division of Clinical Pharmacokinetics; Institute of Pharmacology;
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