title: Unbound fraction of ertapenem in intensive care unit patients.
abstract: OBJECTIVE
  To determine unbound ertapenem concentrations in plasma and to describe the pharmacokinetics of unbound ertapenem in intensive care unit (ICU) patients.
  
  
  METHODS
  For assessing the influence of experimental conditions and for development of the ultrafiltration protocol, plasma from healthy volunteers was used. Concentrations of total and unbound ertapenem were determined by HPLC in 29 plasma samples from six ICU patients treated with 1 g of ertapenem once daily. The concentration-time courses were described by a one-compartment model. Ertapenem binding to albumin was assessed by Michaelis-Menten kinetics in solutions of human serum albumin, in plasma from healthy volunteers and in plasma from ICU patients.
  
  
  RESULTS
  The unbound fraction (fu) of ertapenem was highly susceptible to pH and temperature during ultrafiltration and was ∼20% in plasma from healthy volunteers at clinically relevant concentrations. In ICU patients, fu was substantially higher (range 30.9%-53.6%). The unbound concentrations of ertapenem exceeded 2 mg/L for 72% (median; range 39%-100%) of the 24 h dosing interval and 0.25 mg/L for 100% (range 79%-100%). The number of binding sites per albumin molecule was 1.22 (95% CI 1.07-1.38) in plasma from healthy volunteers and 0.404 (95% CI 0.158-0.650) in samples from ICU patients.
  
  
  CONCLUSIONS
  Determination of unbound ertapenem by ultrafiltration is susceptible to experimental conditions. When determined at physiological pH and temperature, fu of ertapenem is 2- to 4-fold higher than previously reported and even higher in ICU patients. Binding studies indicate that hypoalbuminaemia alone does not explain these differences. This issue should be further investigated for its clinical relevance.
authors: Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany.
authors: Uwe
authors: U
authors: Liebchen
authors: Hospital Pharmacy, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany Department of Pharmaceutical Biology, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany.
authors: Alexander
authors: A
authors: Kratzer
authors: Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169 Berlin, Germany.
authors: Sebastian G
authors: SG
authors: Wicha
authors: Department of Pharmacology, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany.
authors: Frieder
authors: F
authors: Kees
authors: Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169 Berlin, Germany.
authors: Charlotte
authors: C
authors: Kloft
authors: Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169 Berlin, Germany Department of Anaesthesiology and Intensive Care, Charité University Hospital Berlin - Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany martin.kees@charite.de.
authors: Martin G
authors: MG
authors: Kees
mesh_terms: D000900:Anti-Bacterial Agents / Q000097:blood*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D000077727:Ertapenem; D006801:Humans; D007362:Intensive Care Units / Q000592:standards; D011485:Protein Binding / Q000502:physiology; D047090:beta-Lactams / Q000097:blood*
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D000077727:Ertapenem
keywords: carbapenems; pharmacodynamics; pharmacokinetics; protein binding; β-lactams