Abstract
Microdialysis is a pharmacokinetic tool that can be advantageous when obtaining tissues' pharmacokinetic information. Since absolute extracellular tissue concentrations are needed in pharmacokinetic studies, calibrating the microdialysis system is necessary. The internal standard method is superior when compared to other calibration methods. However, thorough evaluation of the internal standard is required before it can be used. In vitro experiments and an in vivo study on pigs (n=8) were conducted to assess the relative recoveries by gain and by loss for piperacillin, both with and without a benzylpenicillin concentration of 5µg/mL. Furthermore, the in vivo setup allowed for an evaluation of piperacillin cancellous bone and subcutaneous tissue concentrations in a single 8h dosing interval. Ultra-high performance liquid chromatography (UHPLC) was used to determine piperacillin and benzylpenicillin concentrations. Relative recovery by loss for benzylpenicillin and relative recovery by gain for piperacillin were similar in in vitro and in vivo. Presence of benzylpenicillin did not affect the relative recovery for piperacillin. Relative recovery, pharmacokinetic parameters and fT>MIC were similar when comparing the retrodialysis by drug and the internal standard calibration methods (p > 0.31). Mean fT>MIC (16µg/mL) for plasma, cancellous bone and subcutaneous tissue were 232min, 255min and 295min, respectively. Our findings suggest that benzylpenicillin is suitable as an internal standard for piperacillin in microdialysis studies. Mean fT>MIC (16µg/mL) for plasma, cancellous bone, and subcutaneous tissue reached a target of 50% fT>MIC under the investigated conditions (mean range: 52%-66%); however, the target was not obtained in all pigs in all compartments. Moreover, 100% fT>MIC was not obtained in any case, suggesting that different strategies must be taken into consideration if higher targets are employed.
Highlights
Microdialysis is a benign pharmacokinetic method allowing for continuous and simultaneous sampling of the free, unbound interstitial space concentrations of antimicrobials from multiple tissue compartments such as bone, soft tissues and solid organs.[1]
Our findings suggest that benzylpenicillin is suitable as an internal standard for piperacillin in microdialysis studies
The in vitro study was designed to answer the following four questions: Question 1) Does recovery by gain (RRgain) equal recovery by loss (RRloss) for piperacillin: similar RRgain and RRloss were found for piperacillin (p = 0.99)
Summary
Microdialysis is a benign pharmacokinetic method allowing for continuous and simultaneous sampling of the free, unbound interstitial space concentrations of antimicrobials from multiple tissue compartments such as bone, soft tissues and solid organs.[1] This is encouraging in antimicrobial pharmacokinetic studies, as the interstitial space most often is considered the active site.[2−5] the microdialysis method serves as a promising alternative to tissue specimens, which previously have been the predominant method for obtaining antimicrobial tissue pharmacokinetics.[6] Using a semipermeable membrane at the tip of the microdialysis catheter, the microdialysis system is driven by diffusion.[2−5] As the microdialysis system is continuously perfused, equilibrium will never occur.[2−5] the concentration in the dialysates only represents a fraction of the actual tissue concentration. Mostly in vitro studies have been performed to validate the internal standard,[8,9] but as shown in other studies in vitro RR does not always reflect in vivo RR.[5,10] This demonstrates, that it is crucial to conduct detailed evaluations in both in vitro and in vivo studies before using the internal standard in microdialysis studies.[5,7,10]
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