Determination of Organ Specific Pharmacokinetic Data for the Anti-Tuberculosis Drugs in Guinea Pigs Using Microdialysis

Lanni, Faye Rachel (2019). Determination of Organ Specific Pharmacokinetic Data for the Anti-Tuberculosis Drugs in Guinea Pigs Using Microdialysis. PhD thesis The Open University.

Abstract

There is a need for innovative and optimised pre-clinical models in the TB drug development pipeline to better predict the pharmacokinetics of candidate anti-TB drugs in vivo to shorten the time taken for novel drugs and treatment combinations to be approved for clinical trial, Microdialysis can be used in awake freely moving animals to describe the pharmacokinetic behaviour of drugs in the organs as a continuous sampling technique. It is the only technique available that collects the unbound pharmacologically relevant portion of the drug. The aim of this PhD was to develop and optimise the microdialysis methodology in the guinea pig model to better understand the pharmacokinetics of anti-TB drugs in the lung.

Meticulous in vitro experiments were performed with each drug before progressing into in vivo experiments because the recovery (concentration of the drug in the tissue fluid related to that in the collected dialysate) of the drug is dependent upon 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 ethambutol, isoniazid and rifampicin at physiologically relevant concentrations. Following identification of a strong correlation between rifampicin concentrations in the clinically relevant lung and the sacrospinalis (site of probe implantation) and confirmation of the calculated probe efficiency (21±9%), an in vivo microdialysis experiment was designed to measure rifampicin concentrations in the sacrospinalis.

Four guinea pigs were dialysed for four hours. Guinea pigs were ear bled and relevant organs taken at necropsy to compare total vs unbound drug concentrations. Blood concentrations did not reflect the concentrations of rifampicin in the organs.

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