Proteinbindungscharakter und Pharmakokinetik von Ertapenem bei Intensivpatienten

Item type:	Thesis of the University of Regensburg (PhD)
Date:	18 April 2017
Referee:	Prof. Dr. Bernd Salzberger
Date of exam:	7 April 2017
Institutions:	Medicine > Lehrstuhl für Innere Medizin I Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert)
Keywords:	Proteinbindung, Pharmakokinetik, Ertapenem, Ultrafiltration, freie Konzentrationen, Beta-Laktam, Carbapenem
Dewey Decimal Classification:	600 Technology > 610 Medical sciences Medicine
Status:	Published
Refereed:	Yes, this version has been refereed
Created at the University of Regensburg:	Yes
Item ID:	35549

Abstract (German)

Diese Arbeit beschreibt die Pharmakokinetik mit besonderer Betrachtung der Proteinbindung von Ertapenem bei Intensivpatienten. Der freie Anteil betrug bei den sechs eingeschlossenen Intensivpatienten 37,8 %. Die Standarddosierung einmal 1g Ertapenem täglich zeigte suffiziente freie Konzentrationen.

Translation of the abstract (English)

OBJECTIVES: To determine unbound ertapenem concentrations in plasma and to describe the pharmacokinetics of unbound ertapenem in intensive care unit (ICU) patients. PATIENTS AND 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 ...

Translation of the abstract (English)

OBJECTIVES:
To determine unbound ertapenem concentrations in plasma and to describe the pharmacokinetics of unbound ertapenem in intensive care unit (ICU) patients.
PATIENTS AND 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.

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