Factors that Influence the Distribution of Antimicrobials into the Interstitial Fluid as Determined by in Vivo Ultrafiltration and Pharmacokinetic Modeling in Dogs

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Title: Factors that Influence the Distribution of Antimicrobials into the Interstitial Fluid as Determined by in Vivo Ultrafiltration and Pharmacokinetic Modeling in Dogs
Author: Bidgood, Tara Lynn
Advisors: Mark G. Papich, Committee Chair
Abstract: Successful treatment of bacterial infections requires achieving antimicrobial concentrations above the minimal inhibitory concentration (MIC) at the site of infection for a sufficient duration of time. Knowledge of pharmacokinetic parameters and the extent of protein binding of antimicrobials are important for designing appropriate dosages. Because only the protein-unbound fraction is microbiologically active, knowledge of the effect of protein binding on drug diffusion into tissues is important for evaluating MIC results in target species. Traditional antimicrobial pharmacokinetic studies have focused on determining plasma concentrations and plasma pharmacokinetic parameters of total (protein bound and unbound) drug concentrations. Since the majority of bacterial infections are in the interstitial fluid (ISF), determining unbound drug ISF concentrations is more relevant for predicting therapeutic efficacy. We conducted three studies to test the hypothesis that the distribution of antimicrobials into the ISF can be accurately predicted from plasma concentrations by determining the extent of plasma protein binding. We compared the distribution of antimicrobials with a range of pharmacokinetic parameters and physicochemical properties that may affect drug distribution, such as protein binding, lipophilicity, systemic clearance, and volume of distribution. We also evaluated an in vivo ultrafiltration device as an alternative method to tissue cages and tissue biopsies for ISF collection. The first study evaluated the plasma and ISF concentrations of meropenem after intravenous (IV) and subcutaneous (SC) administration in dogs. After in vivo ultrafiltration probes were placed SC, ISF and plasma samples were collected simultaneously. The results showed that ISF and plasma (total and unbound) concentrations were similar because meropenem had low protein binding. Drug concentrations at the infection site (i.e., ISF) could be reliably predicted from plasma concentrations. The second study compared plasma (total and unbound) concentrations with ISF concentrations for meropenem and doxycycline during a constant rate infusion (CRI) in dogs. Administering a CRI enabled a comparison of plasma and ISF concentrations at steady state without the influence of drug elimination. In vitro protein binding and lipophilicity was higher for doxycycline compared to meropenem. At steady state there was a significant difference between total plasma and ISF doxycycline concentrations but when protein binding was taken into account, the unbound plasma and ISF concentrations were similar. At steady state there was little difference between meropenem plasma (total and unbound) and ISF concentrations. This study illustrated the strong influence of high plasma protein binding on tissue distribution of unbound drug for a drug such as doxycycline. The third study evaluated the plasma and ISF concentrations of enrofloxacin, its metabolite ciprofloxacin, and marbofloxacin after a CRI and oral administration in dogs. High volume of distribution and lipophilicity has been two characteristics reported as important for distribution to tissues. However, despite a higher volume of distribution and greater lipophilicity, this did not result in increased penetration into the ISF for enrofloxacin compared to marbofloxacin. During steady state there was no statistical difference between unbound plasma and ISF concentrations. The results from the three studies indicated protein binding was the primary determinant of drug distribution into the ISF from plasma. It is the unbound fraction that is microbiologically active and since most bacterial infections are confined to the extracellular space, therapeutic efficacy would be better achieved by designing dosing regimens based on pharmacokinetics of the unbound concentrations in the plasma. The in vivo ultrafiltration device was shown in our studies to be a reliable, minimally invasive, and humane technique for ISF collection in the dog.
Date: 2006-01-09
Degree: PhD
Discipline: Comparative Biomedical Sciences
URI: http://www.lib.ncsu.edu/resolver/1840.16/5025

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