JAC Advance Access originally published online on July 12, 2006
Journal of Antimicrobial Chemotherapy 2006 58(3):632-636; doi:10.1093/jac/dkl284
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Penetration of ertapenem into skeletal muscle and subcutaneous adipose tissue in healthy volunteers measured by in vivo microdialysis
1 Department of Pharmaceutics, College of Pharmacy, University of Florida Gainesville, USA 2 Department of Pulmonary Medicine, Medical School Hannover Hannover, Germany 3 Department of Pharmacy Practice, College of Pharmacy, University of Florida Gainesville, USA 4 Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Medical University of Vienna Vienna, Austria 5 Department of Pharmacology, College of Medicine, University of Florida Gainesville, USA
Received 28 March 2006; returned 15 May 2006; revised 7 June 2006; accepted 15 June 2006
*Corresponding author. Tel: +1-352-846-2726; Fax: +1-352-392-3249; E-mail: hartmut{at}ufl.edu
Objectives: Ertapenem is FDA approved for the treatment of skin and skin-structure infections (SSSI), but its in vivo penetration into the interstitial space of soft tissues is unknown. The present microdialysis study was conducted to measure free, protein-unbound ertapenem concentrations in muscle and subcutaneous tissue.
Volunteers and methods: In a single-centre, prospective, open-label study six healthy volunteers (three females, 22–37 years) were treated with 1 g ertapenem given as a single intravenous dose. Microdialysis and plasma samples were collected before and at different time points up to 12 h after medication. Drug concentrations were determined by a validated LC–MS-MS method.
Results: No serious or microdialysis-associated adverse events were observed. Ertapenem concentrations in plasma reached a maximum (Cmax) of 103.3 ± 26.3 mg/L, a terminal elimination half-life (t1/2) of 3.8 ± 0.6 h and an AUC0–
of 359.7 ± 66.5 mg·h/L. Mean peak concentrations of free, protein-unbound ertapenem in interstitial space fluid of skeletal muscle and subcutaneous adipose tissue were much lower (Cmax = 6.7 ± 4.1 and 4.0 ± 1.6 mg/L, respectively). This degree of tissue distribution is consistent with high concentration-dependent plasma protein binding of ertapenem (84–96%). AUC0– values for both muscle and adipose tissue were lower as well (39.7 ± 24.8 and 18.6 ± 4.6 mg·h/L). However, unbound interstitial fluid concentrations exceeded MIC90 values for the important SSSI pathogens for 7 (subcutis) and 10 h (muscle) after dosing.
Conclusions: These results support the previously observed clinical efficacy of ertapenem in the treatment of SSSI.
Keywords: subcutis , distribution , target site , pharmacokinetics
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