The potential of microdialysis to estimate rifampicin concentrations in the lung of guinea pigs

Faye Lanni*, Neil Burton, Debbie Harris, Susan Fotheringham, Simon Clark, Oliver Skinner, Nathan Wiblin, Mike Dennis, Stuart Armstrong, Geraint Davies, Ann Williams

*Corresponding author for this work

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Abstract

Optimised pre-clinical models are required for TB drug development to better predict the pharmacokinetics of anti-tuberculosis (anti-TB) drugs to shorten the time taken for novel drugs and combinations to be approved for clinical trial. Microdialysis can be used to measure unbound drug concentrations in awake freely moving animals in order to describe the pharmacokinetics of drugs in the organs as a continuous sampling technique. The aim of this work was to develop and optimise the microdialysis methodology in guinea pigs to better understand the pharmacokinetics of rifampicin in the lung. In vitro experiments were performed before progressing into in vivo studies because the recovery (concentration of the drug in the tissue fluid related to that in the collected dialysate) of rifampicin was dependent on a variety of experimental conditions. Mass spectrometry of the dialysate was used to determine the impact of flow rate, perfusion fluid and the molecular weight cut-off and membrane length of probes on the recovery of rifampicin at physiologically relevant concentrations. Following determination of probe efficiency and identification of a correlation between rifampicin concentrations in the lung and skeletal muscle, experiments were conducted to measure rifampicin in the sacrospinalis of guinea pigs using microdialysis. Lung concentrations of rifampicin were estimated from the rifampicin concentrations measured in the sacrospinalis. These studies suggest the potential usefulness of the microdialysis methodology to determine drug concentrations of selected anti-TB drugs to support new TB drug development.

Original languageEnglish
Article number0245922
Number of pages11
JournalPLoS ONE
Volume16
Issue number1
DOIs
Publication statusPublished - 22 Jan 2021

Bibliographical note

Funding Information: This work was supported by the Department of Health, UK. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. Author Neil Burton is affiliated to Q3 Analytical but provided his time for this study for free. Q3 Analytical provided support in the form of salaries for author NB, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.

Open Access: This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publisher Copyright: © 2021 Lanni et al.

Citation: Lanni F, Burton N, Harris D, Fotheringham S, Clark S, Skinner O, et al. (2021) The potential of microdialysis to estimate rifampicin concentrations in the lung of guinea pigs. PLoS ONE 16(1): e0245922.

DOI: https://doi.org/10.1371/journal.pone.0245922

Keywords

  • SKELETAL-MUSCLE
  • TUBERCULOSIS
  • PENETRATION
  • PHARMACODYNAMICS
  • PHARMACOKINETICS
  • AGENTS
  • MODEL

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